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The maternal-to-zygotic transition revisitedNadine L. Vastenhouw1,*, Wen Xi Cao2 and Howard D. Lipshitz2,*
ABSTRACTThe development of animal embryos is initially directed by maternalgene products. Then, during the maternal-to-zygotic transition (MZT),developmental control is handed to the zygotic genome. Extensiveresearch in both vertebrate and invertebrate model organisms hasrevealed that the MZT can be subdivided into two phases, during whichvery different modes of gene regulation are implemented: initially,regulation is exclusively post-transcriptional and post-translational,following which gradual activation of the zygotic genome leads topredominance of transcriptional regulation. These changes in thegene expression program of embryos are precisely controlled andhighly interconnected. Here, we review current understanding ofthe mechanisms that underlie handover of developmental controlduring the MZT.
KEY WORDS: MZT, Genome activation, Maternal mRNAs
IntroductionEarly animal development is controlled by maternal mRNAs andproteins that are loaded into the egg during oogenesis. Theseimplement fundamental molecular and cellular processes, as well asthe specification of initial cell fates and pattern. As developmentproceeds, control is handed over from maternally provided geneproducts to those synthesized from the zygotic genome. Thismaternal-to-zygotic transition (MZT) is characterized by multipleevents, the most striking among which are the elimination of a largesubset of maternal gene products and the onset of transcription fromthe zygote’s genome (Box 1).The MZT has been referred to previously as a ‘play in two acts’
(Tadros and Lipshitz, 2009). Since then, technological advances havedramatically increased our understanding of the MZT. Although itremains a two-act play, many scenes and players have been added,and the plot has become more complex and better understood. Here,we describe how the gene expression program of embryos is shapedduring the MZT. First, we describe the scale and dynamics ofmaternal control, as well as the processes that influence the maternalgene expression program. These include the regulation of maternalmRNA stability and translation, as well as the modulation of proteinstability and functions by post-translational modifications. Then, wediscuss how the zygotic gene expression program is activated. Thisincludes roles for cell cycle length, transcriptional repressors andactivators, and changes in chromatin organization. Finally, wedescribe how and why the maternal and zygotic gene expressionprograms are intertwined with each other to ensure successfulhandover of developmental control from one generation to the next.
Regulation of maternal gene productsRegulation of mRNA stability and clearanceAll animal oocytes are loaded with mRNA species representing alarge fraction of the protein-coding capacity of their genome(summarized in Table 1). Estimates from global analyses suggestthat the maternal transcripts represent a range of the protein-codingtranscriptome, from about one-third in the mouse (Wang et al.,2004) and Caenorhabditis elegans (Baugh et al., 2003; Stoeckiuset al., 2014), to three-quarters in Drosophila melanogaster (DeRenzis et al., 2007; Lécuyer et al., 2007; Tadros et al., 2007;Thomsen et al., 2010), the echinoderm Strongylocentrotuspurpuratus (Wei et al., 2006) and the zebrafish, Danio rerio(Aanes et al., 2011; Harvey et al., 2013). During the MZT, a subsetof the maternal transcripts is cleared from the embryo (Boxes 2 and3). Estimates range from about one-quarter of the maternaltranscripts in zebrafish (Aanes et al., 2011; Bazzini et al., 2012;Harvey et al., 2013; Mishima and Tomari, 2016), one-third inC. elegans and mouse (Baugh et al., 2003; Hamatani et al., 2004),to about two-thirds in Drosophila (Thomsen et al., 2010).
All animal embryos undergo phased maternal mRNA clearance;the initial phase is directed by maternally provided gene productswhereas the later phases require zygotically synthesized products.The scale and dynamics of these phases varies across species, withrespect to both time and developmental stage (Fig. 1; Table 1).Furthermore, technical differences among studies affectquantification (Boxes 2 and 3). Finally, in animals that set asideprimordial germ cells in the early embryo, the MZT differs in somaversus germline (Box 4).
In Drosophila, an early maternally directed wave of decay istriggered upon egg activation and does not require fertilization; thisis followed by one or more waves that require transcription of thezygotic genome and are therefore zygotically directed (Bashirullahet al., 2001; Bashirullah et al., 1999; Tadros et al., 2007; Tadroset al., 2003). About 25% of the cleared transcripts are degradedstrictly by the maternal machinery, 35% strictly through the zygoticmachinery, while 40% show mixed decay effected by both maternaland zygotic mechanisms (Fig. 1A) (De Renzis et al., 2007; Tadroset al., 2007; Thomsen et al., 2010). In C. elegans, about 30% of thematernal mRNAs are targeted for degradation by the one-cell stage,whereas another 30% are degraded starting at the four-cell stage,coinciding with the activation of zygotic transcription (Fig. 1B)(Baugh et al., 2003; Stoeckius et al., 2014).
In the echinoderm S. purpuratus, there appear to be three wavesof maternal transcript degradation, but the role of maternal versuszygotic gene products in directing clearance is unknown (Fig. 1C)(Tu et al., 2014). In zebrafish, of the cleared maternal transcripts,about 60% degrade between the one-cell and 16-cell stages, whilethe remaining 40% degrade subsequently, coinciding with zygotictranscription (Aanes et al., 2011; Mathavan et al., 2005; Mishimaand Tomari, 2016). Expression profiling in zebrafish lacking TATA-binding protein (Ferg et al., 2007) or treated with α-amanitin(Mishima and Tomari, 2016), and therefore unable to undergozygotic genome activation, have shown that the latter wave of
1Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße108, 01307 Dresden, Germany. 2Department of Molecular Genetics, University ofToronto, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
*Authors for correspondence ([email protected]; [email protected])
N.L.V., 0000-0001-8782-9775; H.D.L., 0000-0002-7372-4419
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clearance requires zygotic transcription (Fig. 1D). In Xenopustropicalis, about one-third of the maternal transcripts are clearedbefore the major wave of zygotic genome activation (ZGA) (Tanet al., 2013), while 15% are cleared after ZGA (Fig. 1E) (Graindorgeet al., 2006).In the mouse, the onset of the earliest wave of maternal transcript
degradation is triggered by completion of meiosis (i.e. beforefertilization and thus not pictured in Fig. 1F); a second wave ofdegradation is triggered by fertilization; and a third, zygoticallydirected, wave follows the major activation of the zygotic genomeafter the two-cell stage (Hamatani et al., 2004; Svoboda et al.,2015). Gene expression profiling in human embryos suggests thatthey too undergo at least two waves of maternal transcript clearance(Fig. 1G) (Dobson et al., 2004; Zhang et al., 2009b).As maternal mRNAs can be stable for days, weeks, months or
years in oocytes but are then degraded rapidly in a matter of hoursor, at most, days, understanding this component of theMZT requireselucidation of the mechanisms underlying both long-term transcriptstabilization and rapid transcript destabilization. These processes areregulated by RNA-binding proteins, small non-coding RNAs, RNAmodifications and ‘codon optimality’ (Fig. 2).
RNA-binding proteinsRNA-binding proteins (RBPs) regulate either stabilization of storedmaternal mRNAs in oocytes or their destabilization during the MZT.The particular RBPs that mediate these processes appear to varyacross species (Table 1). However, in general, there have not been anysystematic studies aimed at assessing whether RBPs identified as keyregulators in one species exert similar effects in others.In X. laevis, the Y-box RBP FRGY2 binds without sequence
specificity to maternal mRNAs and functions to translationallyrepress and stabilize them (Bouvet and Wolffe, 1994; Matsumotoet al., 1996). Similarly, the zebrafish Y-box protein, Ybx1, globallyrepresses maternal mRNA translation in oocytes (Sun et al., 2018),and in mouse oocytes, the Y-box protein MSY2 stabilizes maternaltranscripts (Medvedev et al., 2011; Yu et al., 2001; Yu et al., 2002).Here, upon oocyte maturation, MSY2 is phosphorylated by theCDC2A (CDK1) kinase and MSY-bound mRNAs are released(Medvedev et al., 2008). In C. elegans and Drosophila, Y-boxproteins are expressed during oogenesis but a role in transcriptstabilization has not yet been identified (Arnold et al., 2014; Boaget al., 2005; Mansfield et al., 2002). Instead, homologs of the dead-
box helicase Dhh1 (CGH-1 in C. elegans, ME31B in Drosophila)have been implicated in stabilization and translational repression ofmaternal mRNAs (Arnold et al., 2014; Boag et al., 2005; Wanget al., 2017).
The role of RBPs as trans-acting factors that regulate andcoordinate maternal transcript degradation has been particularlywell studied inDrosophila embryos (Fig. 2A). Two RBPs, Smaug, aSAM-domain RBP (Chen et al., 2014; Tadros et al., 2007) andBrain tumor (BRAT), a TRIM-NHL RBP (Laver et al., 2015a),regulate the maternally directed wave of decay. Subsequent,zygotically directed decay can be separated into two phases. Thefirst is driven by miRNAs (Benoit et al., 2009; Bushati et al., 2008)(discussed below). The second is mediated by Brain tumor (BRAT)and possibly also Pumilio (PUM), a PUF-domain RBP (Gerberet al., 2006; Laver et al., 2015a,b; Thomsen et al., 2010). The smaugmRNA itself is translationally repressed during oogenesis by PUMand additional unknown factors; repression is relieved upon eggactivation by the Pan gu (PNG) serine/threonine kinase (Fig. 3A)(Tadros et al., 2007). Smaug binds to hairpin structures in its targetmRNAs (Aviv et al., 2003; Chen et al., 2014; Dahanukar et al.,1999; Semotok et al., 2008; Smibert et al., 1999) and can triggertheir degradation by recruiting the CCR4-NOT-deadenylasecomplex (Fig. 2A) (Semotok et al., 2005). Smaug also repressestarget mRNA translation via recruitment of Argonaute 1 and theeIF4E-binding protein Cup (Nelson et al., 2004; Pinder andSmibert, 2013). The majority of the targets of Smaug are bothrepressed and degraded, while smaller subsets are degraded but notrepressed, or vice versa (Chen et al., 2014; Nelson et al., 2007;Semotok et al., 2005; Semotok et al., 2008). PUM and BRAT bindto single-stranded motifs in their target transcripts (Laver et al.,2015a; Loedige et al., 2014). BRAT directs degradation of hundredsof maternal transcripts via both the maternal and the zygoticpathways (Laver et al., 2015a,b), whereas PUM appears toparticipate predominantly in zygotically directed clearance(Gerber et al., 2006; Laver et al., 2015a,b). In the maternal waveof decay, the targets of BRAT do not significantly overlap withthose of Smaug (Laver et al., 2015a), suggesting that these twoRBPs act independently of each other on distinct subsets of thematernal transcriptome. Interestingly, the smaug mRNA is itselftargeted for degradation at the end of the MZT by BRAT, andpossibly other factors, including PUM (Fig. 3A) (Laver et al.,2015a,b). Smaug, BRAT and PUM all promote transcriptdeadenylation (Newton et al., 2015; Semotok et al., 2005; Temmeet al., 2010; Weidmann et al., 2014). Thus, these RBPs act asspecificity factors that recruit a conserved degradation machinery toclear specific subsets of maternal mRNAs.
Another class of RBPs implicated in maternal mRNA clearancecomprises the AU-rich-element binding proteins (ARE-BPs).ARE-BPs have a role in transcript destabilization during the MZTin C. elegans (D’Agostino et al., 2006; Gallo et al., 2008; Schubertet al., 2000), zebrafish (Rabani et al., 2017) and X. laevis (Detivaudet al., 2003; Graindorge et al., 2006; Paillard et al., 1998; Voeltz andSteitz, 1998), and possibly also mouse (Fig. 2A) (Ramos et al.,2004). Although a motif resembling AREs is enriched inDrosophila mRNAs that are destabilized during the MZT (DeRenzis et al., 2007), a role for ARE-BPs has not yet been identifiedin Drosophila. In Xenopus, ARE-BPs appear to function togetherwith the embryonic deadenylation element binding protein (EDEN-BP, also known as CUGBP1) (Graindorge et al., 2008), whichdirectsmaternal transcript clearance via the recruitment of the poly(A)ribonuclease (PARN) (Moraes et al., 2006). In zebrafish, a recentstudy has implicated hnRNPA1, an RBP that binds to the 3′UTR of
Box 1. The maternal-to-zygotic transition versus themid-blastula transitionThe terms ‘maternal-to-zygotic transition’ (MZT) and ‘mid-blastulatransition’ (MBT) are often used interchangeably in the literature,leading to confusion. Here, we define the MZT and MBT as two distinctconcepts in early embryo development. The MZT describes acoordinated series of molecular events, starting with the degradation ofmaternally deposited transcripts and ending with global activation of thezygotic genome. The MZT can last from a few hours (as in Drosophilaand C. elegans) to days (as in mouse and human). In contrast, the MBTdescribes a specific stage during the development of the embryo, whichis marked by lengthening and desynchronization of the cell cycles. Forexample, following rapid and synchronous cleavage cycles, the MBToccurs at cycle 10 in zebrafish, at cycle 12 in Xenopus and at cycle 14 inDrosophila. There are several cases where the MBT does not coincidewith completion of the MZT. As examples, in Ascaris suum the MZT iscompleted long before its MBT (Wang et al., 2014), whereas, inDrosophila, the MBT is completed before the final wave of maternalmRNA decay (Laver et al., 2015a,b).
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0 00 12 24
1362Cleavage cycle
Time (h)
F Mouse Mus musculus
0 30 2 4
6613Cleavage cycle
Time (h)
E Frog Xenopus tropicalis
Cleavage cycleTime (h)
00 1
8 213
314
A Insect Drosophila melanogaster
1.6 2.40.80Cleavage cycle
Time (h) 01 3 5
B Nematode Caenorhabditis elegans
D Fish Danio rerio
83.712
2.320
5.314
0 1Cleavage cycleTime (h)
0 00 16 32
1482Cleavage cycle
Time (h)
G Human Homo sapiens
16 2481Cleavage cycle
Time (h) 0~7 ~8 ~10
C Echinoderm Strongylocentrotus
purpuratus
Fig. 1. The maternal-to-zygotic transition (MZT). Red curves depict destabilized maternal transcripts; red gradients represent timing of the multiple phases oftranscript degradation. Blue curve depicts transcription from the zygotic genome; blue gradient represents a gradual increase ingene numbers transcribedduring ZGA.Schematics depicting embryo developmental stages for each organism are shown above the corresponding cleavage cycle and time, after fertilization. (A)Drosophilamelanogaster, (B)Caenorhabditis elegans, (C)Strongylocentrotus purpuratus, (D)Danio rerio, (E)Xenopus tropicalis, (F)Musmusculus and (G)Homo sapiens. Thefirst wave of decay in mammals occurs prior to fertilization and is, therefore, not depicted. Adapted, with permission, from Tadros and Lipshitz (2009).
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Table1.
Sca
lean
dregu
latio
nof
materna
ltrans
cripts
Spe
cies
Materna
llyload
edmRNA
cove
rage
(%of
geno
me)
Stabilization
and/or
repres
sion
ofmRNAs
intheoo
cyte
mRNAclea
ranc
e(%
ofmaterna
l)
Mec
hanism
ofmaterna
lmRNAclea
ranc
e
RNA-binding
and/or
asso
ciated
proteins
SmallR
NAs
Cod
onus
eRNAmod
ifica
tions
C.e
lega
ns∼35
%(Bau
ghet
al.,20
03;
Stoec
kius
etal.,20
14)
CGH-1
(Arnoldet
al.,20
14;
Boa
get
al.,20
05)
∼30
%(Bau
ghet
al.,20
03;S
toec
kius
etal.,20
14)
MEX-5/6
(ARE-BP)
(D’Ago
stinoet
al.,20
06;G
alloet
al.,
2008
;Sch
uberte
tal.,
2000
)
End
o-siRNA*
(Stoec
kius
etal.,20
14)
Not
stud
ied
Not
stud
ied
D.m
elan
ogas
ter
∼75
%(Tad
roset
al.,20
07;
Tho
mse
net
al.,20
10)
ME31
B*
(Wan
get
al.,20
17)
∼60
%(Tho
mse
net
al.,20
10)
Smau
g(C
henet
al.,20
14;T
adroset
al.,
2007
)
Pum
ilio
(Gerbe
ret
al.,20
06;L
aver
etal.,
2015
a;La
veret
al.,20
15b)
Brain
Tum
or(Lav
eret
al.,20
15a)
ARE-BP*
(DeRen
ziset
al.,20
07)
miR-309
(Bus
hatiet
al.,20
08)
Other
miRs*
(Luo
etal.,20
16)
piRNAs*
(Rou
gete
tal.,
2010
;Barck
man
net
al.,
2015
)
Yes
(ME31
B?)*
(Baz
zini
etal.,
2016
)
Not
stud
ieddu
ring
theMZT
D.rerio
∼70
%(Aan
eset
al.,20
11;
Harveyet
al.,20
13)
YBX1
(Sun
etal.,20
18)
>25
%(Aan
eset
al.,20
11;H
arve
yet
al.,20
13;M
ishimaan
dTom
ari,20
16)
hnRNPA*
(Des
picet
al.,20
17)
PUM*
(Rab
anie
tal.,
2017
)
ARE-BP*
(Rab
anie
tal.,
2017
)
miR-430
(Baz
zini
etal.,20
12;
Gira
ldez
etal.,20
06)
Yes
(DDX6?
)(Baz
zini
etal.,
2016
;Mishima
andTom
ari,20
16)
N6-m
ethy
lade
nosine
(Zha
oet
al.,20
17)
Terminal
uridylation
(Cha
nget
al.,20
18)
Xen
opus
Not
stud
ied
FRGY2
(X.lae
vis)
(Bou
veta
ndWolffe
,199
4;Matsu
motoet
al.,19
96)
Not
stud
ied
ARE-BP
(X.lae
vis)
(Voe
ltzan
dSteitz,1
998;
Morae
set
al.,20
06)
miR-427
(X.lae
vis)
(Lun
det
al.,20
09)
Yes
(DDX6?
)*(X.lae
vis)
(Baz
zini
etal.,
2016
)
Terminal
uridylation
(X.lae
vis)
(Cha
nget
al.,20
18)
CUGBP1/EDEN-BP
(X.tropica
lis)(G
raindo
rgeet
al.,
2008
;Morae
set
al.,20
16)
M.m
uscu
lus
∼40
%(W
anget
al.,20
04)
MSY2
(Med
vede
vet
al.,20
11;
Yuet
al.,20
01;Y
uet
al.,20
02)
∼33
%(H
amatan
ieta
l.,20
04)
BTG4
(Yuet
al.,20
16)
ZFP36
L2(ARE-BP)
(Ram
oset
al.,20
04)
End
o-siRNA*
(Ohn
ishi
etal.,20
10;
Stein
etal.,20
15)
Yes
(DDX6?
)*(Baz
zini
etal.,
2016
)
N6-m
ethy
lade
nosine
(Iva
nova
etal.,20
17)
Terminal
uridylation
(Cha
nget
al.,20
18)
*Predicted
throug
hindirect
eviden
cebu
tadirect
mec
hanism
inmaterna
lmRNAregu
latio
nno
texp
erim
entally
show
n.
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maternal transcripts through an AGGGA motif, in clearance of asubset of maternal mRNAs after ZGA (Despic et al., 2017).In the mouse, the oocyte-expressed protein BTG4, although not
itself anRBP, links eIF4E to theCCR4-NOT-deadenylase complex totrigger degradation of maternal mRNAs that are actively translated(Fig. 2A) (Yu et al., 2016). Embryos from female Btg4−/− miceproduce oocytes that complete meiosis but fail to clear maternaltranscripts. Reminiscent of the case for Drosophila smaug mutants,zygotically transcribed genes are downregulated and the embryos failto develop to the two-cell stage (Yu et al., 2016). Furthermore, also
reminiscent of smaug mRNA translation at egg activation beingdependent on the PNG kinase (Tadros et al., 2007), translation ofBTG4 protein is triggered by activation of the MAP kinases ERK1and ERK2 during meiotic maturation (Yu et al., 2016).
Small non-coding RNAsSmall non-coding RNAs that have been implicated in theMZT includemicroRNAs (miRNAs), which are processed from primary transcriptsproduced by miRNA-encoding genes (reviewed by Gebert andMacRae, 2019), PIWI-interacting RNAs (piRNAs; PIWI, P-element
A RNA-binding and/or RNA-associated proteins
B Small RNAs
C RNA modifications
D Codon use
D. melanogaster D. rerio M. musculus
N6-methyladenosine
m7G
AAAAAm6AYTHDF2
?
N6-methyladenosine
m7G
AAAAAm6AYTHDF2
?
?
Endo-siRNA
RISC
m7G
AAAAA
SMG
AAAAASRE
CCR4/NOT
m7G
PUMAAAAA
PUM motif
CCR4/NOT
m7G
AAAAA
BRAT
BRAT motif
CCR4/NOT
m7G
*hnRNPA1
AAAAAAGGGA
m7G eIF4G
BTG4
m7G
eIF4E
AAAAA
CCR4-NOT
*ARE-BP
AAAAAAU-rich element
m7G
Terminal uridylation
m7G
AAAAAUU
TUT4/7
Terminal uridylation
m7G
AAAAAUU
TUT4/7
Slow ribosomes
m7G
AAAAA
ME31b?
Slow ribosomes
m7G
AAAAA
DDX6?
Slow ribosomes
m7G
AAAAA
DDX6?
miR-309 Other miRs? piRNAs?
AGO1RISC
m7G
AAAAA
CCR4/NOT
miR-430
RISC
m7G
AAAAA
CCR4/NOT
*ARE-BP
AAAAAUUA/poly-U
m7G
*PUMAAAAA
PUM motif
m7G
*ARE-BP
AAAAAAU-rich element
m7G
D. melanogaster D. rerio M. musculus
D. melanogaster D. rerio M. musculus
D. rerio M. musculus
Fig. 2. Mechanisms of maternal transcriptdegradation in model organisms. Severalmechanisms directing maternal transcriptdegradation are compared acrossD. melanogaster, D. rerio and M. musculus.(A) The best-studied RNA-binding proteins(RBPs) for each organism are shown. Smaug(SMG), Pumilio (PUM), Brain tumor protein(BRAT), AU-rich binding element protein(ARE-BP) and Heterogeneous nuclearribonucleoprotein A1 (hnRNPA1). Theirhomologs across organisms have largely notbeen studied and are omitted from this figure.B-cell translocation gene 4 (BTG4) in mouse,though not an RBP, is shown because it triggerstranscript degradation by recruiting theCCNR4-NOT-deadenylase complex.(B) MicroRNAs direct maternal transcript decayvia the Argonaute (AGO1)/RNA-inducedsilencing complex (RISC) in Drosophila andzebrafish; they are present but may not play arole in the mouse (therefore, not shown) whereendo-siRNAs may instead function. (C) RNAmodifications, such as N6-methyladenosine(m6A) and terminal uridylation, promote decaythrough the action of YTH N6-MethyladenosineRNA Binding Protein 2 (YTHDF2) and TerminalUridylyl Transferase 4/7 (TUT4/7), respectively.Analogous modifications have been found inD. melanogaster, but their functions during theMZT have not been investigated. (D) Codonoptimality directs maternal transcript stability inD. melanogaster, D. rerio and M. musculus, butthe mechanism for this regulation has only beenstudied in yeast thus far; homologs of yeastDhh1p (ME31B, DDX6) are shown. Asterisksindicate enrichment of cis-elements, whereasthe RBPs have not yet been investigated.Question marks indicatewhere trans-factors areknown but mechanisms have not been studiedin detail (Table 1).
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induced wimpy testis), which are derived from transposable elementsresident in the genome (reviewed by Czech et al., 2018), andendogenous small interferingRNAs (endo-siRNAs),which are derivedfrom double-stranded hybrids of mRNAs or transposable elements(reviewed by Piatek and Werner, 2014) (Table 1).The most well studied are miRNAs, which play a crucial role in
directing the zygotic wave of maternal transcript decay in multiplespecies (Fig. 2B). In zebrafish, the miR-430 family of miRNAs isexpressed during early ZGA and is required for translationalrepression, deadenylation and decay of about 40% of the maternaltranscripts that are cleared during the MZT (Fig. 2B) (Bazzini et al.,2012; Giraldez et al., 2006). An orthologous mechanism exists duringthe X. laevis MZT through its miR-430 ortholog, miR-427. As inzebrafish, miR-427 is expressed zygotically and mediates thedeadenylation and clearance of maternal transcripts (Lund et al.,2009). An analogous pathway exists in Drosophila, mediated byzygotic transcription of miRNAs from themiR-309 cluster, which arerequired for the degradation of 14% of transcripts undergoing the latewave of decay (Fig. 2B) (Bushati et al., 2008). Zygotic expression ofmore than 70 species of miRNAs, including the miR-309 family,depends on the Smaug RBP (Benoit et al., 2009; Luo et al., 2016). Insmaug mutants, failure to produce these miRNAs results instabilization of a large number of maternal transcripts that arenormally cleared in the zygoticwave of decay (Benoit et al., 2009; Luoet al., 2016). Thus, Smaug functions directly to clearmaternalmRNAsprior to ZGA and indirectly to clear maternal transcripts after ZGA(Fig. 3A). The Drosophila zygotic miRNAs do not bear sequencehomology to vertebratemiR-430/miR-427, suggesting that microRNAtargeting of the maternal transcriptome during the MZT may havearisen independently in the vertebrate and invertebrate lineages.piRNAs have also been implicated in maternal transcript decay in
Drosophila (Barckmann et al., 2015; Dufourt et al., 2017; Rougetet al., 2010) where hundreds of maternal mRNAs have beenreported to co-purify with PIWI, Argonaute 3 and Aubergine, and tobe targeted by the piRNA pathway for degradation (Barckmannet al., 2015).Endo-siRNAs (‘22G-RNAs’) have been shown to clear a subset of
maternal mRNAs from early C. elegans embryos (Stoeckius et al.,2014). Although miRNAs and endo-siRNAs are present, miRNAactivity appears to be suppressed in mouse oocytes and earlyembryos, and removal of DGCR8, which is essential formiRNA biogenesis, has no effect on preimplantation development(Ohnishi et al., 2010; Suh et al., 2010; Tang et al., 2007). It is possible
that endo-siRNAs serve as regulators of maternal mRNA clearance(Fig. 2B) (Lykke-Andersen et al., 2008); however, conditionalremoval of AGO2 from mouse oocytes results in failure to completemeiosis, preventing analyses in early embryos (Stein et al., 2015).
RNA modificationsOver the past few years, it has become clear that chemicalmodifications of mRNAs either during or after their synthesis canplay a role in determining their fate. N6-methylation of adenosine(m6A), for example, can cause a structural switch in RNA thatcontrols accessibility to protein-binding motifs (Liu et al., 2015).In zebrafish embryos, more than one-third of maternal mRNAspecies are methylated on adenosine (Zhao et al., 2017). The m6A-binding protein YTHDF2 is required for clearance of almost half ofthe maternal mRNAs that are degraded early in the MZT, as well asover one-quarter of those that are degraded later (Fig. 2C) (Zhaoet al., 2017). Maternal YTHDF2 is also required for clearance of asubset of the transcriptome of the mouse oocyte (Ivanova et al.,2017). However, at least in zebrafish, not all methylated RNAs aredestabilized, and not all transcripts that are degraded in aYTHDF2-dependent manner are methylated (Zhao et al., 2017).The exact mechanisms of regulation and the interplay betweenm6A-directed decay, and other pathways of transcript clearance,remain to be elucidated.
Another form of mRNA modification during the vertebrate MZTis terminal uridylation of the poly(A) tail of an mRNA (Chang et al.,2018). In zebrafish, Xenopus and mouse, terminal uridylation of thetranscriptome increases greatly during the MZT and promotes rapiddecay of a subset of transcripts with short poly(A) tails (Fig. 2C)(Chang et al., 2018).
Codon optimalityIn unicellular organisms, ‘optimal’ codons are defined as those withhigh cognate tRNA abundance, whereas non-optimal codons for thesame amino acid have low cognate tRNA levels (Hanson and Coller,2018). In yeast, the DEAD-box protein Dhh1p preferentially targetstranscripts enriched for non-optimal codons by associating with
Box 2. Gene expression analysisTo precisely measure changes in RNA levels during the MZT, severalgene expression analysis methods can be used, each of which has itstheir own benefits and caveats. RNA sequencing provides genome-widequantitative information. However, as regulation of poly(A) tail length isan important component of the MZT, the most accurate quantification ofRNA levels requires total RNA-sequencing after depletion of rRNAsrather than poly(A) RNA-sequencing, which biases reads towardstranscripts with long poly(A) tails and, therefore, underestimates thenumber of transcript species present (Collart et al., 2014). An alternativeto RNA sequencing is the Nanostring approach, which providesinformation on fewer transcripts but allows for precise quantificationwithout the need to fragment, amplify or reverse transcribe the RNA(Geiss et al., 2008). Nanostring analysis has proven especially useful indetecting low-abundance zygotic transcripts against a background ofenormous amounts of maternal RNA (Joseph et al., 2017; Sandler andStathopoulos, 2016), which is often hard to achieve using (non-targeted)RNA-sequencing methods.
Box 3. Temporal and spatial analysis of the MZTTo distinguish between maternal and zygotic transcripts that are oftenpresent at the same time, zygotic contributions have been removed bytranscription inhibition (Lee et al., 2013), the use of chromosomaldeficiencies (De Renzis et al., 2007) or the analysis of activatedunfertilized eggs (Bashirullah et al., 2001; Bashirullah et al., 1999;Tadros et al., 2007; Tadros et al., 2003). Conversely, to analyzezygotically transcribed RNA, newly synthesized RNAs have beenspecifically labeled, isolated and sequenced (Chan et al., 2018preprint; Heyn et al., 2014), single nucleotide variations betweenstrains have been used to identify transcription from the paternalgenome (Harvey et al., 2013; Lott et al., 2011) or intron signal has beenused as amarker of de novo transcription (Lee et al., 2013). The analysisof transcript levels in (pools of) whole embryos provides transcriptinformation averaged over all cells of the embryo. Spatial information canbe obtained by sequencing embryo sections (Combs and Eisen, 2013;Junker et al., 2014) or single-cell sequencing of dissociated cells (Briggset al., 2018; Farrell et al., 2018), which can be mapped back onto theembryo based on markers with a known expression pattern.Alternatively, transcripts can be visualized either in fixed or liveembryos (Campbell et al., 2015; Perez-Romero et al., 2018; Stapelet al., 2018; Stapel et al., 2016). Although low throughput, this providesthe best spatial information and can be quantitative when singletranscripts can be detected (Stapel et al., 2016).
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slow-moving ribosomes and directing these transcripts for degradation(Presnyak et al., 2015; Radhakrishnan et al., 2016). Studies inzebrafish have found preferential degradation during the MZT oftranscripts enriched for non-optimal codons (Bazzini et al., 2016;Mishima and Tomari, 2016), a process that may also occur in mouse,Xenopus andD.melanogaster (Bazzini et al., 2016) (Fig. 2D). It is notyet known whether proteins homologous to Dhh1p (DDX6 in mouseand fish, and ME31B in Drosophila) function in this process.
Regulation of maternal mRNA translationDuring Drosophila egg activation (i.e. at the beginning of its MZT),translational efficiency increases for up to 50% of maternal mRNAsand decreases for up to 20%, as measured by ribosome footprinting(Kronja et al., 2014b). The translation of maternal transcripts has alsobeen profiled in mouse, where 20% of the maternal transcriptome issignificantly depleted from polysomes during oocyte maturation,whereas 17% of the maternal transcriptome is significantly enriched(Chen et al., 2011). There is a direct correlation between poly(A) taillength and translational efficiency in early embryos of zebrafish, X.laevis and Drosophila (Eichhorn et al., 2016; Subtelny et al., 2014).These correlations diminish upon ZGA and are not found in non-embryonic tissue types across several species (Subtelny et al., 2014).Thus, the poly(A) tail may play a role in the regulation of translationprimarily in transcriptionally silent stages.Themechanisms of cytoplasmic polyadenylation and activation of
maternal mRNA translation were first shown in X. laevis oocytes.Upon maturation, the Aurora kinase triggers binding of cytoplasmicpolyadenylation element binding protein (CPEB) to cytoplasmicpolyadenylation specificity factor (CPSF) and the mRNA. Together,they displace the PARN deadenylase and recruit the GLD2 poly(A)polymerase (Barnard et al., 1993; Cao and Richter, 2002; Groismanet al., 2002; Hake and Richter, 1994; Kim and Richter, 2006;Stebbins-Boaz et al., 1999). This results in poly(A) tail lengtheningand translational activation. After fertilization, a subset of maternaltranscripts undergoes CPEB-mediated polyadenylation in theembryo prior to zygotic transcription, likely regulating the firstwave of translational activation (Collart et al., 2014). However, themechanisms regulating polyadenylation in the X. tropicalis embryo
have yet to be determined. The CPEB protein family also coordinatescytoplasmic polyadenylation and translation in zebrafish, wheremore than 40% of maternal mRNAs undergo cytoplasmicpolyadenylation in early embryos (Winata et al., 2018). Thetranslation of these transcripts increases during the MZT, whereasthere is a decrease in translation of transcripts lacking elongatedpoly(A) tails (Winata et al., 2018). CPEB1 also functions duringmouse oocyte maturation; ERK1/2 phosphorylation of CPEB1causes polyadenylation-mediated translation of BTG4 and otheressential maternal proteins, such as the cell cycle regulator, Cyclin Band the DAZL RBP (Sha et al., 2017). DAZL, in turn, directstranslational activation during oocyte maturation (Chen et al., 2011;Fukuda et al., 2018). Autoregulation of its own mRNA by DAZLestablishes a positive feedback loop together with CPEB1, whichensures the progression ofmeiosis and proper translational activation(Sousa Martins et al., 2016).
In early Drosophila embryos, the Wispy (GLD2) cytoplasmicpoly(A) polymerase directs polyadenylation of maternal mRNAsand is essential for the MZT (Benoit et al., 2008; Cui et al., 2008;Cui et al., 2013; Salles et al., 1994). However, relative changes inpoly(A) tail length and translational efficiency are retained even inthe absence of Wispy. Thus, the current hypothesis is that selectiveshortening, rather than lengthening of poly(A) tails serves as themajor determinant of maternal mRNA translation at this stage(Eichhorn et al., 2016). Furthermore, in Drosophila, PNG triggerspolyadenylation and translation at the beginning of the MZT(Fig. 3A) (Tadros et al., 2007; Vardy and Orr-Weaver, 2007). Morethan 60% of the maternal mRNAs that undergo either increases ordecreases in translation depend on the PNG kinase for theseprocesses (Kronja et al., 2014b). The Smaug RBP serves as a majormediator of PNG-dependent repression, with most of this repressionattributable to poly(A) tail shortening (Eichhorn et al., 2016).However, cytoplasmic polyadenylation is not sufficient to rescuetranslation in png mutants, presumably because PNG must alsorelieve repression by specific RBPs such as PUM (Tadros et al.,2007; Vardy and Orr-Weaver, 2007).
Cytoplasmic polyadenylation and deadenylation also play keyroles in regulation of mRNA stability and translation in C. elegans(Fig. 3B) (Millonigg et al., 2014; Nousch et al., 2017; Nousch et al.,2013; Nousch et al., 2014). During oocyte maturation and the MZT,the translational status of hundreds of transcripts is coordinated byLIN-41, a TRIM-NHL RBP related to Drosophila BRAT. Actingantagonistically to LIN-41 are the RBPs, OMA-1 and OMA-2,which are related to the Tristetraprolin/TIS-11 ARE-BP (Tsukamotoet al., 2017). LIN-41 and the OMAs also interact with both theGLD-2 poly(A) polymerase and the CCR4-NOT-deadenylase(Tsukamoto et al., 2017). Combinatorial action of LIN-41, OMAsand GLD-2 in distinct RNP complexes may direct a repression-to-activation switch for specific target transcripts, which in turnencode RBPs that function in early embryogenesis (Tsukamotoet al., 2017).
In summary, during the MZT, cytoplasmic polyadenylation anddeadenylation affect both the stability and translation of mRNAs.While the machinery for these processes is conserved, the particularRBPs that confer specificity on subsets of transcripts vary acrossspecies. Likewise, whereas protein kinases play a key role intriggering translational derepression of maternal mRNAs, theidentity of these kinases varies across species.
Post-translational regulation of maternal proteinsDespite the documented importance of post-transcriptional regulationof maternal transcripts at the level of mRNA translation and stability,
Box 4. The MZT in primordial germ cellsIn animals that set aside primordial germ cells (PGCs) in their earlyembryos, there is additional spatial and temporal control of the MZT inthe PGCs relative to the soma. In C. elegans the smaller, posterior (P)product of the first cell division gives rise to the PGCs. ZGA is initiated bythe four-cell stage in the soma, while transcription remains silenced in theP-cell lineage due to the presence of a global transcriptional repressor,PIE-1 (Seydoux et al., 1996). The germ plasm at the posterior of theDrosophila embryo buds off to give rise to PGCs within which bothmaternal transcript degradation and ZGA are delayed relative to thesoma (Siddiqui et al., 2012). In the PGCs, as in the soma, both maternalmRNA clearance and ZGA are abrogated in smaug mutants (Siddiquiet al., 2012). Transcriptional repression in theDrosophilaPGCs dependson the Polar Granule Component protein, PGC, which blockstranscription elongation (Hanyu-Nakamura et al., 2019; Hanyu-Nakamura et al., 2008). In echinoderms, the PGCs (small micromeres)are formed from asymmetric divisions by the 32-cell stage. Clearedmaternal transcripts in the somatic cells are ‘protected’ in the smallmicromeres due to degradation of the Cnot6 transcript, which encodesan essential component of the CCR4-NOT-deadenylase complex(Oulhen and Wessel, 2016; Wessel et al., 2014). In zebrafish, PGC-expressed nanos1 and tdrd7 are protected from miR-430-mediatedtranscript degradation by the germline-expressed RBP Dead end 1(Dnd1) (Kedde et al., 2007; Mishima et al., 2006).
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global transcriptome and proteome analyses prior to and during theMZT have revealed that post-translational regulation of proteinstability and function also play a major role in Drosophila (Beckeret al., 2018; Casas-Vila et al., 2017; Kronja et al., 2014a) and C.elegans (Stoeckius et al., 2014). For example, inC. elegansmore thanone-quarter of the transcriptome is downregulated at least twofold inearly embryos, whereas only 5% of the proteome shows a similardecrease (Stoeckius et al., 2014). These results highlightthe importance of an additional level of regulation at the post-translational level, through modifications that affect maternal proteinstability and function, which is essential for the progression of oocytematuration and the MZT (Liu et al., 2018a).One highly conserved mechanism of post-translational regulation
that combines phosphorylation and ubiquitin-dependent proteolysisoccurs at the beginning of the MZT (reviewed by Pesin andOrr-Weaver, 2008). Most animals are arrested during meiosis by thepresence of Cyclin B. Release from meiotic arrest is achieved bythe anaphase-promoting complex (APC), a cyclin-dependent E3ubiquitin ligase complex that is phosphorylated and activated uponfertilization to target Cyclin B for degradation.About 30% of the oocyte proteome is estimated to change in
phosphorylation state during Drosophila egg activation (Krauchunaset al., 2012). The PNG kinase complex, which plays a key role inpost-transcriptional regulation of maternal mRNAs, undergoessuch a change (Fig. 3A) (Hara et al., 2017). In Drosophila oocytes,the regulatory subunit, GNU, is phosphorylated by CYCB/CDK1,which blocks the binding of GNU to the kinase subunit. Degradationof CYCB by the APC during meiotic completion triggersdephosphorylation of GNU, which then binds to and activatesthe PNG kinase subunit. Subsequently, PNG phosphorylatesGNU, leading to GNU degradation and the inactivation of thecomplex (Hara et al., 2017). This temporally coordinatedactivation and self-inactivation tightly restricts the activity ofthis kinase to a short window during the early MZT, ensuringprecise post-translational control of its phosphorylation targets.The PNG kinase is essential for translation of the Smaug RBP inthe early embryo (discussed above). However, Smaug is rapidlycleared a couple of hours later, at the end of the MZT (Benoit et al.,2009). Indeed, towards the end of the MZT, not only Smaug butalso additional global post-transcriptional regulators, such asME31B, Cup and TRAL, undergo among the largest decreases inabundance in the entire proteome (Sysoev et al., 2016; Wang et al.,2017). Although the mechanisms that direct clearance of theseproteins are not yet known, they represent a striking example ofhow post-translational regulation has a major impact on post-transcriptional regulation during the MZT.Another example of post-translational regulation comes from
C. elegans (Fig. 3B). In early embryos, maternally supplied OMA-1and OMA-2 are phosphorylated by the DYRK kinaseMBK-2, whichallows binding to the transcription factor TAF-4, thus sequestering itin the cytoplasm and preventing premature ZGA (Guven-Ozkanet al., 2008). By the four-cell stage, phosphorylated OMA-1 andOMA-2 are ubiquitylated by accumulating levels of the Cullin-RINGE3 ubiquitin ligase (CRL), leading to degradation of the OMAsand release of TAF-4, which is then imported into the nucleuswhere it directs zygotic transcription (Guven-Ozkan et al., 2008).Post-translational regulation is important for inactivation andclearance of additional post-transcriptional regulators during theC. elegans MZT. The LIN-41, GLD-1 and CPB-3 RBPs are allcleared by the SCFSEL-10 E3 ubiquitin ligase (Kisielnicka et al., 2018;Spike et al., 2018). However, the signaling pathways that triggerinactivation and clearance of these RBPs differ: the CDK1 kinase
pathway clears LIN-41, while the MAP kinase pathway clearsGLD-1 (Spike et al., 2018).
In the mouse pre-implantation embryo, massive degradation ofmaternal proteins by autophagy is triggered by fertilization and isrequired for progression of early embryogenesis (Tsukamoto et al.,2008). While proteomic studies have identified the ubiquitin-proteasome pathway to be important during pre-implantationdevelopment as a whole (Zhang et al., 2009a), the first specificrole for this pathway during the MZT has only recently beencharacterized. The TAB1 kinase inhibits the action of the NFκBtranscription factor by retaining it in the cytoplasm. In earlyembryos, the E3 ubiquitin ligase RnF114 directs degradation ofTAB1, permitting translocation of NFκB into the nucleus and, thus,activation the NFκB pathway, which is essential for development(Yang et al., 2017). Indeed, either knockdown of RnF114 orpersistence of TAB1 protein prevents development beyond thetwo-cell stage (Yang et al., 2017).
Regulation of zygotic transcriptionScale and dynamics of zygotic transcriptionThe second act of the MZT is the onset of zygotic transcription.Historically, two transcriptional waves have been distinguished: aminor wave that occurs during the cleavage divisions; and a majorwave that, in many species, coincides with the lengthening of thecell cycle. Genome-wide gene expression analysis, however, hasrevealed that ZGA does not consist of two distinct waves, butinstead reflects a period over which transcription is graduallyactivated (Fig. 1) (Aanes et al., 2011; Collart et al., 2014; Harveyet al., 2013; Heyn et al., 2014; Lott et al., 2011; Owens et al., 2016;Pauli et al., 2012; Sandler and Stathopoulos, 2016; Tan et al., 2013;White et al., 2017).
In terms of the embryonic mitotic cell cycles, human, mouse andsea urchin start transcription the earliest, with the first zygotictranscripts being detected at the one-cell stage (Abe et al., 2015;Aoki et al., 1997; Gildor and Ben-Tabou de-Leon, 2015; Hamataniet al., 2004; Materna et al., 2010; Yan et al., 2013) (Table 2).In C. elegans, Xenopus, zebrafish and Drosophila, the first zygotictranscripts are detected in cell cycles 2, 3, 6 and 8, respectively(Chan et al., 2018 preprint; Collart et al., 2014; De Renzis et al.,2007; Edgar et al., 1994; Hadzhiev et al., 2019; Heyn et al., 2014;Hilbert et al., 2018 preprint; Kimelman et al., 1987; Kwasnieskiet al., 2019 preprint; Lécuyer et al., 2007; Lott et al., 2011; Mathavanet al., 2005; Owens et al., 2016; Paranjpe et al., 2013; Seydoux andFire, 1994; Skirkanich et al., 2011; Tan et al., 2013; Yanai et al., 2011;Yang et al., 2002), although there is some genetic evidence thattranscription may begin earlier in Drosophila (Ali-Murthy et al.,2013). In terms of absolute time, the very rapid cleavage cycles ofthe early Drosophila, Xenopus and zebrafish embryos mean that,in these species, ZGA begins several hours earlier than in themouse (Fig. 1).
During genome activation, a significant fraction of all genes inthe genome is transcribed: 5% in X. tropicalis (Collart et al., 2014;Tan et al., 2013),∼10% in C. elegans (Baugh et al., 2003),∼20% inmouse (Hamatani et al., 2004), ∼25% in zebrafish (Aanes et al.,2011; Harvey et al., 2013; Lee et al., 2013) and∼35% inDrosophila(De Renzis et al., 2007; Kwasnieski et al., 2019 preprint; Lécuyeret al., 2007; Lott et al., 2011) (Table 2). Although different sets ofgenes are activated in different species (Heyn et al., 2014), theproteins these genes encode are often enriched for transcriptionfactors and other developmental regulators, such as microRNAs(Collart et al., 2014; De Renzis et al., 2007; Lee et al., 2013). Someof these are important for the degradation of maternally loaded
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RNAs (Bushati et al., 2008; Giraldez et al., 2006; Lund et al., 2009),and others for the transcription of subsequently activated genes(Collart et al., 2014). For most genes, the onset of transcriptionduring ZGA is stochastic, which means that not all cells start toactivate that gene at the same time (Boettiger and Levine, 2009;Stapel et al., 2017). This initially results in large cell-to-celldifferences in gene expression levels, which could – in principle –
hamper development (Lagha et al., 2013). Uniform patterns of geneexpression, however, are reached by spatial averaging, such as in theDrosophila syncytium (Little et al., 2013), or temporal averaging, asin zebrafish (Stapel et al., 2017), thus overcoming this problem.
Although some of the genes that are activated during ZGA arestrictly zygotic (i.e. not maternally provided), many othersare loaded maternally and then re-expressed in the embryo.
Developmental time
B Caenorhabditis elegans
A Drosophila melanogaster
Degradationby SCFSel-10
Phosphorylationby MBK
OMA1/2
TAF-4
TFIID
OMA1/2P Degradation
by CRL E3
TAF-4
TFIID
ZGA
LIN-41
OMA1/2
LIN-41
Cytoplasm
Nucleus
Oocyte transcripts
Maternal smg mRNA
PUMX
ZGA
Cytoplasm
NucleusZygotic miRNAs
PNG
PLUGNU
PNG
PLU GNUP
Activation by dephosphorylation
SMG
Inactivation by self-phosphorylation
PNG
PLU GNUPP
PLU
GNU
PNG
Maternal mRNAs
mRNA degradation
Translation of transcriptional
repressors
Repressor
Maternal smg mRNA
Indirect SMG target mRNAsDirect SMG target mRNAs
mRNA degradation
Maternal smg mRNA
PUM?BRAT
Translationalrepression
mRNA degradation
BRAT?PUMX BRAT? Y
Fig. 3. Interplay of post-transcriptional and post-translational regulation during the maternal-to-zygotic transition (MZT). (A) In D. melanogaster,the RNA-binding protein (RBP), Pumilio (PUM) and additional factors, possibly including Brain tumor protein (BRAT) and an unknown factor, X, represstranslation of the smaug mRNA in the oocyte. The PNG-PLU kinase complex is inactive due to phosphorylation-mediated dissociation of its regulatory subunit,GNU. Upon egg activation, dephosphorylation of GNU activates PNG, directing derepression of smaug translation. The PNG kinase phosphorylates GNU,inactivating the complex and targeting it for degradation. Accumulating Smaug (SMG) protein directs the degradation and translational repression of a largenumber of maternal transcripts, allowing zygotic genome activation (ZGA). Early ZGA includes transcription of zygotic miRNAs, which direct the degradationof additional maternal transcripts. The smaug transcript itself is targeted for degradation near the end of the MZT by BRAT and possibly additional factors, such asPUM and unknown factor Y. (B) In C. elegans, LIN-41, OMA-1 and OMA-2 act antagonistically to regulate transcripts in the oocyte. LIN-41 is degradedduring oocyte maturation by the E3 ubiquitin ligase complex SCFSel-10. Additionally, phosphorylation of OMA-1 and OMA-2 by the MBK-2 kinase duringoocyte maturation results in binding and sequestering of the TAF-4 transcription factor in the cytoplasm, inhibiting ZGA in the early embryo. By the four-cell stage,degradation of phosphorylated OMA-1 and OMA-2, by accumulating levels of the CRL E3-ubiquitin ligase, releases TAF-4, which is then imported into thenucleus where it binds the transcriptional factor TFIID to mediate ZGA. Adapted, with permission, from Tadros and Lipshitz, 2009.
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Table2.
Sca
lean
dregu
latio
nof
zygo
tictran
scripts
Spe
cies
Firs
tzyg
otic
tran
scrip
tsde
tected
(cell/n
uclear
cyclenu
mbe
r)
Zyg
oticallyex
pres
sed
mRNAco
verage
(%of
gene
s)*
Strictly
zygo
tically
expres
sed
mRNAco
verage
(%of
zygo
tic)
Fac
tors
invo
lved
inZGA
Cellc
ycle
leng
th
Gen
eral
tran
scrip
tiona
lrepres
sors
Spe
cific
tran
scrip
tiona
lrepres
sors
Trans
criptio
nal
activators
Chrom
atin
structure‡
C.e
lega
nsCellcycle
2(Edg
aret
al.,19
94;
Sey
doux
andFire
,199
4)
∼10
%(Bau
ghet
al.,20
03)
Not
stud
ied
Not
stud
ied
Not
stud
ied
Not
stud
ied
TAF-4
(Guv
en-O
zkan
etal.,
2008
)
Not
stud
ied
D.m
elan
ogas
terNuc
lear
cycle8§
(DeRen
ziset
al.,20
07;
Lécu
yere
tal.,
2007
;Lotte
tal.,20
11)
∼35
%(D
eRen
ziset
al.,20
07;
Lécu
yeret
al.,20
07;
Lottet
al.,20
11;
Kaw
sniesk
ieta
l.,20
19prep
rint)
∼33
%(D
eRen
ziset
al.,
2007
)
No (F
arrellan
dO’Farrell20
13;
McC
leland
andO’Farell,20
08;
Blythean
dWiesc
haus
,201
5;Pritch
ardan
dSch
ubiger,1
996)
Not
stud
ied
TTK (Brownan
dWu,
1993
;Pritch
ard
andSch
ubiger,
1996
)
Zelda (Harris
onet
al.,20
11;
Lian
get
al.,20
08;
Nienet
al.,20
11)
Not
stud
ied
D.rerio
Cellcycle
6(C
hanet
al.,20
18prep
rint;
Had
zhievet
al.,20
19;H
eyn
etal.,20
14;H
ilberte
tal.,
2018
prep
rint;Matha
vanet
al.,20
05)
∼25
%(Aan
eset
al.,20
11;
Harve
yet
al.,20
13;
Leeet
al.,20
13)
∼25
%(Lee
etal.,20
13)No (D
alle
Nog
areet
al.,20
09;
Zha
nget
al.,20
14a)
Histone
s(Jos
ephet
al.,
2017
)
Not
stud
ied
POU5F
3,SOX19
Ban
dNANOG
(Lee
etal.,20
13;
Leichs
enrin
get
al.,20
13;
Jose
phet
al.,20
17)
H3K
27Ac
(Cha
net
al.,20
18prep
rint;Zha
nget
al.,20
18;S
atoet
al.,
2019
prep
rint)
Xen
opus
Cellcycle
3(X.lae
vis)
(Yan
aiet
al.,20
11;
Kim
elman
etal.,19
87;
Skirkan
ichet
al.,20
11;
Yan
get
al.,20
02)
Cellcycle
3(X.tropica
lis)
(Yan
aiet
al.,20
11;
Paran
jpeet
al.,20
13;
Owen
set
al.,20
16;C
ollart
etal.,20
14;T
anet
al.,
2013
)
∼5% (X
.tropica
lis)
(Collartet
al.,20
14;
Tan
etal.,20
13)
Not
stud
ied
Yes (X
.lae
vis)
(Collartet
al.,20
13;K
imelman
etal.,19
87)
Histone
s(X.lae
vis)
(Alm
ouzn
iand
Wolffe
,199
5;Amod
eoet
al.,
2015
)
Kaiso (X.lae
vis)
(Ruz
ovet
al.,20
04;
Ruz
ovet
al.,20
09)
xDnm
t1(X.lae
vis)
(Dun
ican
etal.,
2008
)
TBP (X.lae
vis)
(Vee
nstraet
al.,19
99)
H3R
8me
(X.lae
vis)
(Blytheet
al.,20
10)
M.m
uscu
lus
Cellcycle
1(Abe
etal.,20
15;A
okieta
l.,19
97;H
amatan
ieta
l.,20
04)
∼20
%(H
amatan
ieta
l.,20
04)Not
stud
ied
Not
stud
ied
Not
stud
ied
Not
stud
ied
Nfy,D
ux,D
ppa2
andDpp
a4(D
eIaco
etal.,20
17;
Hen
drickson
etal.,20
17;
Luet
al.,20
16;D
eIaco
etal.,20
19;E
ckersley-
Mas
linet
al.,20
19)
H3K
4me3
(Aoshimaet
al.,20
15;
Dah
leta
l.,20
16;
Liuetal.,20
16;Z
hang
etal.,20
16;B
ultm
anet
al.,20
06)
*Num
bers
arehigh
lyaffected
bymetho
dsan
dcu
t-offs
used
indiffe
rent
stud
ies(see
also
Box
es2an
d3).
‡Weha
veon
lyindica
tedch
ange
sin
chromatin
acce
ssibility
that
have
been
show
nto
affect
theon
seto
ftrans
criptio
n.Pleas
ereferto
thetext
formorech
ange
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In Drosophila, for example, only about one-third of the zygotictranscripts are purely zygotic (De Renzis et al., 2007) and inzebrafish 25% (Lee et al., 2013) (Table 2). In its simplest form,zygotic transcription of genes that are also maternally loadedprovides an opportunity to reinforce the expression of specificgenes. In Drosophila and zebrafish, however, many genesencode distinct maternal and zygotic mRNA isoforms throughdifferential promoter usage, splicing and/or polyadenylation siteusage (Aanes et al., 2013; Atallah and Lott, 2018; Haberle et al.,2014). In these cases, transcription does not just reinforce geneexpression, it also changes the characteristics of transcripts andtherefore their regulation. Functionally, maternal mRNAdegradation and zygotic transcription are used to generate
localized patterns of expression (Combs and Eisen, 2013; DeRenzis et al., 2007; Lécuyer et al., 2007; Vopalensky et al., 2018).
Mechanisms of zygotic genome activationNext, we explore the effect of cell cycle length, transcriptionalrepressors, transcriptional activators, and chromatin accessibility onthe change from transcriptional repression to transcriptional activation(Table 2). We end by proposing a mechanism for the onset oftranscription that takes all of these aspects into account (Fig. 4).
Cell cycle lengthThe early stages of development in insects, amphibians and fishare characterized by rapid cleavage divisions. Because DNAreplication generally interferes with transcription (Rothe et al.,1992; Shermoen and O’Farrell, 1991), rapid cell cycles may reducetranscriptional output during the early stages of development.Indeed, lengthening the cell cycle causes a premature onset oftranscription in X. laevis (Collart et al., 2013; Kimelman et al.,1987), suggesting that genome activation may be a consequenceof cell cycle lengthening. However, similar experiments inzebrafish and Drosophila have not caused premature transcription(Farrell and O’Farrell, 2013; McCleland and O’Farrell, 2008;Zhang et al., 2014a). In fact, in Drosophila embryos, cell cyclelengthening depends on the onset of zygotic transcription (Blytheand Wieschaus, 2015; Pritchard and Schubiger, 1996) arguingagainst a dependence of transcription on cell cycle lengthening inthese species. Thus, it remains unclear to what extent thelengthening of the cell cycle influences the onset of transcriptionduring embryogenesis. What is clear, is that cell cycle lengthaffects the length and number of transcripts that are produced inDrosophila and zebrafish embryos (Edgar and Schubiger, 1986;Hadzhiev et al., 2019; Rothe et al., 1992; Dalle Nogare et al., 2009).Indeed, in these species, the first genes that are expressed duringZGA are often short and lack introns (Heyn et al., 2014; Kwasnieskiet al., 2019; Rothe et al., 1992). Thus, cell cycle length has an effecton the length and number of transcripts that are produced, but itremains enigmatic whether it has a direct effect on the onsetof transcription.
It should be noted that a recent study in Drosophila has shownthat the presence of ‘aborted’ truncated transcripts with intronicsequences from long genes is extensive during ZGA (Kwasnieskiet al., 2019 preprint). Moreover, truncation of long transcripts can beprecisely regulated and, if translated, their gene products could havedevelopmental functions (Sandler et al., 2018). For example, theSex lethal (SXL) RNA-binding protein directs formation of ashortened mRNA isoform of short gastrulation (sog), whichencodes a dominant-negative SOG protein that may prevent TGF-β signaling during this stage of the MZT (Sandler et al., 2018). Thegenerality of regulated and functional truncation of transcriptsencoded by long genes remains to be determined.
Transcriptional repressorsMany proteins are maternally loaded to support embryonicdevelopment during the early cleavage stages. Among these areproteins that repress transcription (Table 2). In X. laevis andDrosophila, for example, sequence-specific repressors have beenidentified that inhibit the expression of subsets of genes (Brown andWu, 1993; Dunican et al., 2008; Pritchard and Schubiger, 1996;Ruzov, 2004; Ruzov et al., 2009). In Drosophila, the transcriptionfactor Tramtrack (TTK) is maternally loaded and represses thetranscription of the segmentation gene fushi tarazu ( ftz) (Brown andWu, 1993; Pritchard and Schubiger, 1996). Reducing the amount of
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Fig. 4. Mechanisms of transcriptional activation during the second act.Chromatin structure is relatively open during the early stages of development,which likely supports the large-scale transcriptional reprogramming thattakes place during ZGA. This suggests that the absence of transcriptionalactivity is not due to a repressive chromatin structure. Approaching ZGA,the genome becomes more compacted overall, while local accessibilityincreases. At the same time, at least in zebrafish andX. laevis, the concentrationof non-DNA-bound histones drops, which allows increasing levels of (generaland gene-specific) transcription factors to successfully compete for DNAbinding. Similarly, the loss of specific repressors allows for transcription ofspecific genes. While the increase in local accessibility facilitates the bindingof transcription factors, accessibility, in turn, often depends on the binding ofspecific transcription factors. Thus, the loss of repressors, the accumulationof activators and local changes in chromatin accessibility together primethe genome for activation. The chromatin accessibility and the balance ofrepressors and activators both influence transcription activity.
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TTK or the number of TTK-binding sites results in premature ftztranscription, while increasing the amount of TTK has the oppositeeffect. Interestingly, the Smaug RBP is required for destruction ofmaternal ttk mRNA, thus providing a link between clearance ofmaternal mRNAs and ZGA (Benoit et al., 2009).In addition to specific repressors, histones have been identified as
more general repressors of transcription in X. laevis and zebrafish(Almouzni and Wolffe, 1995; Amodeo et al., 2015; Joseph et al.,2017). Histones are present in large excess in early embryos(Adamson andWoodland, 1974; Anderson and Lengyel, 1980); theybind with high affinity and little sequence specificity to DNA(Campos and Reinberg, 2009), and, when bound in the form ofnucleosomes, they block access of the transcriptional machinery toDNA (Lorch et al., 1987; Workman and Kingston, 1998). Inzebrafish and Drosophila embryos, the concentration of solublehistones in the nucleus drops in the approach to genome activation(Joseph et al., 2017; Shindo and Amodeo, 2019). Moreover,experiments in zebrafish have revealed that the drop in theconcentration of soluble histones in the nucleus provides anopportunity for the transcriptional machinery to successfullycompete for DNA access and activate transcription (Joseph et al.,2017; Pálfy et al., 2017). Developmental changes in the early embryoprovide at least two mechanisms by which the concentration ofhistones may be reduced during embryogenesis. First, theexponential increase in DNA during the rapid cleavage divisionsmight titrate out histones. A role for DNA content in regulatingthe onset of transcription is supported by experiments in whichincreasing DNA content results in premature onset of transcription inX. laevis, zebrafish and Drosophila (Dekens et al., 2003; Jevtic andLevy, 2017; Lu et al., 2009; Newport and Kirschner, 1982; Prioleauet al., 1994). However, the quantification of both histones and DNAcontent has shown that, at least in zebrafish, the increase in DNAcontent is not sufficient to titrate the levels of soluble histonessignificantly (Joseph et al., 2017). Another possible explanation forthe decrease in nuclear histone concentration involves a change in thenuclear import dynamics of histones. This could be a consequence ofthe dilution of import machinery caused by the increasing number ofnuclei (Shindo and Amodeo, 2019) or of the marked increase in theratio of nuclear over cytoplasmic volume during the cleavage stages(Joseph et al., 2017). The latter has been suggested to limit thecapacity of the nucleus to concentrate proteins (Kim and Elbaum,2013a,b; Kopito and Elbaum, 2007; Kopito and Elbaum, 2009),changing the distribution of histones between nucleus and cytoplasm.A role for import dynamics is supported by the observation that anexperimentally induced increase in nuclear volume results in earliergenome activation in X. laevis (Jevtic and Levy, 2015; Jevtic andLevy, 2017). We conclude that both specific and general repressorsplay a role in changing the balance from transcriptional repression totranscriptional activation during ZGA.
Transcriptional activatorsThe general absence of transcription during early embryogenesis, aswell as the gene-specific onset of transcription that follows, areaffected by the availability of the transcriptional machinery. Asdescribed above, in C. elegans, the general TAF-4 transcriptionfactor is unavailable for transcription during the early stages ofdevelopment (Guven-Ozkan et al., 2008), because the protein issequestered by the binding of OMA-1 and OMA-2. Not until theirphosphorylation at the four-cell stage, is TAF-4 released and able totranslocate into the nucleus, permitting the onset of transcription(Guven-Ozkan et al., 2008). Similarly, in X. laevis, theconcentration of the general TBP transcription factor is limiting
before ZGA (Veenstra et al., 1999). Protein expression profiling hasrevealed that TBP levels increase and reach sufficiently high levelsfor genome activation as a result of translation of maternally storedTBP transcripts (Veenstra et al., 1999). Thus, the lack of generaltranscription factors in the early stages of development contributesto the general absence of transcriptional activity.
Following this period, the gene-specific onset of transcriptionrequires gene-specific transcription factors. The transcription factorsthat activate zygotically expressed genes have been identified inseveral species, including Drosophila (Zelda), zebrafish (Pou5f3,Sox19b, Nanog), human (OCT4, DUX4) andmouse (Dppa2, Dppa4,Nfy, Dux) (De Iaco et al., 2019; De Iaco et al., 2017; Eckersley-Maslin et al., 2019; Gao et al., 2018; Harrison et al., 2011;Hendrickson et al., 2017; Lee et al., 2013; Leichsenring et al., 2013;Liang et al., 2008; Lu et al., 2016; Nien et al., 2011). A recent reviewprovides details of their mechanisms of action (Schulz and Harrison,2018). In Drosophila and zebrafish, RNA encoding these factors ismaternally loaded and their protein levels increase during the earlycell cycles due to translation (Harrison et al., 2010; Harrison et al.,2011; Lee et al., 2013; Nien et al., 2011). In zebrafish, it has beenshown that the levels of such gene-specific transcription factors affectthe time at which transcription starts (Joseph et al., 2017). In thiscontext, it is interesting to note that, in Drosophila and zebrafish,zygotic transcription begins in two distinct areas in the nucleus(Blythe and Wieschaus, 2016; Chan et al., 2018 preprint; Chen et al.,2013; Hadzhiev et al., 2019; Hilbert et al., 2018 preprint; Hug et al.,2017), which may cause a local increase in the concentration oftranscription factors, thereby facilitating transcription.
Chromatin accessibilityChromatin regulates the accessibility of the genome for DNA-binding proteins. Thus, chromatin accessibility is key totranscriptional regulation. In its simplest form, chromatin consistsof DNA wrapped around octamers of the core histone proteinsjoined by a histone linker protein. DNA accessibility is regulatedthrough DNAmethylation, nucleosome positioning and the stabilityof nucleosomes, which in turn is regulated by histone modificationsand the presence of histone variants. Here, we discuss changes inglobal and local chromatin accessibility that accompany genomeactivation, and their role in activating transcription.
Overall, chromatin structure is relatively open during thetranscriptionally inactive period of the MZT. Human and mousegenomes, for example, undergo global DNA demethylation uponfertilization (Guo et al., 2014; Li et al., 2018; Peat et al., 2014; Santoset al., 2002; Shen et al., 2014), but this has not been observed in otherspecies.More generally, the open chromatin structure of early embryosis characterized by highly dispersed chromatin (Ahmed et al., 2010;Popken et al., 2014), the absence of heterochromatin domains (Ancelinet al., 2016; Laue et al., 2019; Mutlu et al., 2018), the absence oftopologically associated domains (‘TADs’) (Du et al., 2017; Hug et al.,2017; Kaaij et al., 2018; Ke et al., 2017; Ogiyama et al., 2018), highlevels of histone acetylation (Adenot et al., 1997; Li et al., 2014) andhigh chromatin mobility (Boškovic et al., 2014). During ZGA, thegenome becomes more compact, which may be related to thereplacement of embryonic linker histone variants with somatic variantsaround this time (Pérez-Montero et al., 2013; Saeki et al., 2005).
In contrast, local genome accessibility increases during genomeactivation in Drosophila, zebrafish, mouse and human (Blythe andWieschaus, 2016; Gao et al., 2018; Li et al., 2018; Liu et al., 2018b;Lu et al., 2016; Wu et al., 2016; Wu et al., 2018). This isaccompanied by the appearance of specific histone modifications.In X. laevis embryos, for example, Histone 3 Arginine 8 (H3R8)
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methylation poises genes for expression (Blythe et al., 2010).Similarly, Histone 3 Lysine 4 trimethylation (H3K4me3), a markthat is generally associated with active transcription, appears onpromoters during genome activation in Drosophila (Chen et al.,2013; Li et al., 2014), X. tropicalis (Hontelez et al., 2015; Lindemanet al., 2011), zebrafish (Vastenhouw et al., 2010; Zhang et al.,2014b) and mouse (Dahl et al., 2016; Zhang et al., 2016) embryos,often prior to transcription. Although in most cases the relevance ofH3K4me3 has not yet been investigated directly, studies in mousehave revealed that it is required for the onset of transcription(Aoshima et al., 2015; Dahl et al., 2016; Liu et al., 2016; Zhanget al., 2016), which supports the observation that Brg1, which isrequired for H3K4 methylation, is necessary for ZGA (Bultmanet al., 2006). Finally, acetylation of Histone 3 Lysine 27 (H3K27Ac)precedes ZGA in zebrafish (Chan et al., 2018 preprint; Sato et al.,2019 preprint; Zhang et al., 2018), and is required for thetranscription of – at least – miR-430, which is one of the first genesto be transcribed. Although there is clearly a role for local histonemodifications in ZGA, no local DNAmethylation changes have beenobserved that coincide with the onset of transcription (Jiang et al.,2013; Kaaij et al., 2016; Potok et al., 2013), arguing against a role forDNA methylation in regulating ZGA. DNA methylation patterns,however, do play a role in the regulation of transcription duringembryogenesis. In zebrafish, for example, hypermethylation atenhancers predicts transcription factor binding and enhancer activity(Kaaij et al., 2016; Liu et al., 2018b), whereas low levels of DNAmethylation at promoters predict H3K4me3 and promoter activity(Andersen et al., 2012; Liu et al., 2018b). Finally, ZGA coincides witha significant increase in both the repressive histone modificationH3K27me3 (Akkers et al., 2009; Hontelez et al., 2015; Li et al., 2014;Lindeman et al., 2011; Liu et al., 2016; van Heeringen et al., 2014;Vastenhouw et al., 2010) and DNA methylation (Potok et al., 2013),which may help to ensure the onset of gene-specific transcription(Potok et al., 2013; Zenk et al., 2017).Taken together, chromatin structure is relatively open during the
early stages of embryogenesis, which likely supports the large-scaletranscriptional reprogramming that takes place during ZGA (Fig. 4).Indeed, the removal of mouse LSD1, which results in prematureheterochromatin formation, interferes with developmentalprogression (Ancelin et al., 2016). Thus, the absence oftranscriptional activity is likely not due to a repressive chromatinstructure. Approaching ZGA, the genome becomes more compactedoverall, while local accessibility increases. At the same time, at leastin zebrafish and X. laevis, the concentration of non-DNA-boundhistones drops (Amodeo et al., 2015; Joseph et al., 2017), whichallows increasing levels of transcription factors to successfullycompete for DNA binding (Joseph et al., 2017; Pálfy et al., 2017).Similarly, the loss of specific repressors allows for transcription ofspecific genes. Although the increase in local accessibilityfacilitates the binding of transcription factors, accessibility, inturn, often depends on the binding of specific transcription factors(Gao et al., 2018; Liu et al., 2018b; Lu et al., 2016; Schulz et al.,2015; Sun et al., 2015; Veil et al., 2019). Thus, the loss ofrepressors, the accumulation of activators and local changes inchromatin accessibility together prime the genome for activation.
Concluding remarksWe now have a reasonably thorough descriptive and mechanisticunderstanding of the two ‘acts’ of the MZT. Maternally loaded geneproducts are required to control early development, while theregulated onset of transcription is required for developmentalprogression: if transcription is inhibited, embryos arrest prior to
gastrulation (Kane et al., 1996; Lee et al., 2013; Zamir et al., 1997).It remains mysterious, however, why such a large fraction of thegene products encoded by the maternal genome is loaded into theegg and then largely eliminated. One clue as to why maternalmRNAs and proteins are cleared may come from the fact thatmaternal and zygotic transcripts from the same gene often representdifferent mRNA isoforms (Aanes et al., 2013; Atallah and Lott,2018; Haberle et al., 2014). Where the isoforms differ inuntranslated regions, these would impose differential regulation oftranscript stability, translation and localization. Where they differ inthe open reading frame, there may also be differences in maternalversus zygotic protein structure and function. Another clue derivesfrom the observation that zygotically re-expressed genes inDrosophila are enriched for ones whose zygotic expression ispatterned (De Renzis et al., 2007). This implies that degradation ofubiquitous maternal transcripts followed by patterned zygotic re-expression is a mechanism that imposes spatial regulation ofprocesses that underlie differential cell behavior and fate in thedeveloping embryo.
Another possible function of degradation of maternal mRNAs andproteins is to supply nutrients to the developing embryo. Evidence forthis comes from studies in the Drosophila embryo, where maternallysupplied dNTPs are insufficient for completion of the DNAreplication and nuclear divisions that occur prior to large-scaleZGA, thus requiring de novo dNTP synthesis fromNTPs (Song et al.,2017). Calculations using previous measurements in oocytes ofXenopus and S. purpuratus have revealed similar dNTP shortages forthe cleavage divisions (Song et al., 2017). Thus, degradation ofmaternally loaded mRNAs may provide a source of nucleotides tosupport DNA replication. Consistent with a requirement for NTPs,rather than a specific set of mRNAs, the maternally loadedtranscriptome shows more variability across species than that ofmost other developmental stages in Drosophila and zebrafish(Atallah and Lott, 2018; Domazet-Lošo and Tautz, 2010; Kalinkaet al., 2010). Furthermore, inDrosophila, the maternal transcripts thatare degraded during theMZT are much less conserved than those thatremain after the onset of ZGA (Atallah and Lott, 2018).
Mechanistically, the regulation of maternal gene productsand the activation of zygotic transcription are highly interrelated.For example, in zebrafish, transcription factors that increase inabundance during the early stages of the MZT, because of translationof maternal mRNAs, are required for ZGA (Lee et al., 2013).Similarly, in Drosophila, the Zelda transcription factor, which isessential for early ZGA, increases in abundance early in the MZTthrough translation of its cognate maternal mRNA (Nien et al., 2011).Additional proteins that increase in abundance show enrichment forfunctions in chromatin organization (Kronja et al., 2014b) andtherefore might play a role in ZGA. Clearance and/or repression ofmaternal gene products appears also to be a prerequisite for ZGA. InC. elegans, for example, degradation of OMA-1 and OMA-2 arerequired to permit nuclear translocation of TAF-4 and, thus, ZGA(Guven-Ozkan et al., 2008). Likewise, mutants that fail to clear and/orrepress a significant fraction of the maternal transcriptome either failto undergo, or suffer a severe delay in, ZGA (e.g.Drosophila smaug,mouse Btg4) (Benoit et al., 2009; Luo et al., 2016; Yu et al., 2016).Finally, genome activation is itself required for the clearance of a largesubset of maternal RNAs. For example, in zebrafish, X. laevis andDrosophila, ZGA produces sets of miRNAs that feed back todestabilize subsets ofmaternal mRNAs (Bushati et al., 2008; Giraldezet al., 2006; Lund et al., 2009). If ZGA does not occur (e.g. inDrosophila smaug mutants or in zebrafish if transcription ischemically inhibited) then the miRNAs are not synthesized and
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their target transcripts persist (Benoit et al., 2009; De Renzis et al.,2007; Lee et al., 2013).
AcknowledgementsWe thank members of the Vastenhouw lab, as well as Jan Brugues, for criticallyreading the manuscript; Edlyn Wu for help with Fig. 4; and the reviewers forhelpful feedback.
Competing interestsThe authors declare no competing or financial interests.
FundingOur research on the MZT is supported by grants from the Max-Planck-Gesellschaft(N.L.V.), the Human Frontiers Science Program (N.L.V.), the VolkswagenFoundation (N.L.V.), the Canadian Institutes of Health Research (H.D.L.), and theNatural Sciences and Engineering Council of Canada (H.D.L.). W.X.C. has beensupported, in part, by an Ontario Graduate Scholarship and by University of TorontoOpen Graduate Scholarships.
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