Noncoding RNA-mediated regulation in innate and adaptive
immunity R. Michael Sheetz, PhD Center for Computational
Sciences
Slide 2
The immune system and how it works Pathogenic agents represent
a constant threat to any organism. In response, mammals (and
insects) have evolved a complex network of specialized cells and
humoral factors capable of controlling and eliminating these
pathogens. The immune system is composed of two key components the
innate immune system and the adaptive immune system.
Slide 3
Pathogenic agents represent a constant threat to any organism.
In response, mammals (and insects) have evolved a complex network
of specialized cells and humoral factors capable of controlling and
eliminating these pathogens. The immune system is composed of two
key components the innate immune system and the adaptive immune
system. Innate immunity provides the host with a first line of
defense against infection by inducing both inflammatory responses
and antimicrobial pathways. The innate immune system also plays a
key role in the initiation and subsequent direction of the adaptive
immune system. The immune system and how it works
Slide 4
Pathogenic agents represent a constant threat to any organism.
In response, mammals (and insects) have evolved a complex network
of specialized cells and humoral factors capable of controlling and
eliminating these pathogens. The immune system is composed of two
key components the innate immune system and the adaptive immune
system. Innate immunity provides the host with a first line of
defense against infection by inducing both inflammatory responses
and antimicrobial pathways. The innate immune system also plays a
key role in the initiation and subsequent direction of the adaptive
immune system. Adaptive immunity, which exhibits a delay of 4 to 7
days before its initial response takes effect, evolved to provide a
more versatile means of defense as well as increased protection
against subsequent re-infection by the same pathogen. Adaptive
immunity is induced in response to the presence of a foreign
antigen and, in contrast to innate immunity, is mediated by the
clonal selection of two classes of antigen-specific WBCs
(B-lymphocytes and T-lymphocytes). The immune system and how it
works
Slide 5
Key cellular components of the innate immune system Neutrophils
PMN cells recruited to the site of infection, phagocytose and kill
invading; also contribute to collateral tissue damage that occurs
during inflammation Macrophages function in phagocytosis,
extracellular killing of infected or altered self target cells,
contribute to tissue repair, and act as antigen-presenting cells
(APCs) Mast cells associated with wound healing and defense against
pathogens; often associated with allergy and anaphylaxis; when
activated, release histamine- and heparin- rich granules and
chemotactic cytokines into the environment. Basophiles /
Eosinophils when activated, basophils release histamine (in defense
against parasites), and play a role in allergic reactions (such as
asthma) when activated, eosinophils secrete a range of highly toxic
proteins and free radicals effective in killing bacteria and
parasites (also responsible for tissue damage occurring during
allergic reactions) NK (natural killer) cells NK cells
nonspecifically kill virus infected and tumor cells.
Slide 6
Dendritic cells DCs main function as antigen presenting cells
whose main function is to process antigen material and present it
on the cell surface to the T cells of the immune system. DCs serve
as a link between the innate and adaptive immune systems.
Conventional dendritic cells express the toll-like receptors TLR2
and TLR4 and secrete interleukin 12 (IL 12) Plasmacytoid dendritic
cells (pDCs) express the TLRs TLR7 and TLR9 and secrete high
amounts of interferon-alpha (IFN ) Key cellular components of the
innate immune system Toll-like receptors TLRs represent a type of
pattern recognition receptor (PRR) and recognize molecules broadly
shared by pathogens collectively referred to as pathogen-associated
molecular patterns (PAMPs).
Slide 7
Key cellular components of the adaptive immune system T cells
meditate effective immune responses by recognizing antigen through
cell-surface T-cell receptors (TCRs). T cells also express one of
two cell-surface glycoproteins that are important for TCR
signalling, CD4 or CD8. These co-receptor proteins bind invariant
regions of MHC class II (CD4) and class I (CD8) molecules, and
contribute to TCR-signal transduction through their interactions
with membrane-associated signaling molecules. Bosselut, R. Nature
Reviews Immunology 4, 529-540 (2004)
Slide 8
Expression of CD4+ T cells are MHC class II restricted and
function as T helper (Th) cells when activated, assisting effector
components of the immune system (such as B cells) through cytokine
secretion and upregulation of expression of specific membrane
ligands. By contrast, CD8+ T cells are MHC class I restricted and
after activation, acquire cytotoxic properties that allow them to
directly kill cells expressing their target antigen. Lazarevic, V.
et al. Nature Reviews Immunology 13, 777-789 (2013)
Slide 9
The inflammatory response is the first line of defense against
infection and the capacity to repair and restore damaged tissues.
If unchecked, a prolonged or inappropriately scaled inflammation
can be detrimental to the host and lead to disease such as
atherosclerosis, arthritis and cancer. The acute inflammatory
response is initiated when pattern recognition receptors (PRRs)
present on the surface of phagocytic macrophages recognize and bind
common constituents of the surface of a pathogen (e.g., bacterium)
triggers a set of signaling cascades that leads to rapid, dynamic
and temporally regulated changes in the expression of hundreds of
genes involved in antimicrobial defense, phagocytosis, cell
migration, tissue repair and the regulation of adaptive
immunity.
Slide 10
The inflammatory response is the first line of defense against
infection and the capacity to repair and restore damaged tissues.
If unchecked, a prolonged or inappropriately scaled inflammation
can be detrimental to the host and lead to disease such as
atherosclerosis, arthritis and cancer. The acute inflammatory
response is initiated when pattern recognition receptors (PRRs)
present on the surface of phagocytic macrophages recognize and bind
common constituents of the surface of a pathogen (e.g., bacterium)
triggers a set of signaling cascades that leads to rapid, dynamic
and temporally regulated changes in the expression of hundreds of
genes involved in antimicrobial defense, phagocytosis, cell
migration, tissue repair and the regulation of adaptive immunity.
Phagocytosis of the pathogen induces the macrophage to secrete both
cytokines and chemokines Cytokines increase the permeability of
blood vessels (allowing fluid and proteins to pass into the
tissues) and activate T cells, whereas chemokines direct the
migration of neutrophils and monocytes from the bloodstream to the
site of infection. The accumulation of fluid and cells at the site
of infection causes the redness, swelling, heat, and pain, known
collectively as inflammation
Slide 11
This change in gene expression involves multiple layers of
regulation that vary depending on the cell lineage involved and the
specific signal that is encountered. This regulation of gene
expression occurs both at the level of transcription and
post-transcription and includes mRNA splicing, mRNA
polyadenylation, mRNA stability, and protein translation. The
complexity of this regulation allows fine-tuning of both the
strength and the duration of the immune response. Within this
complexity of immune regulation, non-coding RNAs (both miRNAs and
lncRNAs) have emerged as key components in the regulation of both
innate and adaptive immunity.
Slide 12
This change in gene expression involves multiple layers of
regulation that vary depending on the cell lineage involved and the
specific signal that is encountered. This regulation of gene
expression occurs both at the level of transcription and
post-transcription and includes mRNA splicing, mRNA
polyadenylation, mRNA stability, and protein translation. The
complexity of this regulation allows fine-tuning of both the
strength and the duration of the immune response. Within this
complexity of immune regulation, non-coding RNAs (both miRNAs and
lncRNAs) have emerged as key components in the regulation of both
innate and adaptive immunity. Post-transcriptional regulation in
innate and adaptive immunity alternative splicing alternative
polyadenylation change in mRNA stability change in translation
initiation change in translation elongation
Slide 13
Possible consequences of alternative splicing during pre-mRNA
processing Approximately one-fifth of the genes expressed in human
dendritic cells (DCs) undergo alternative splicing upon bacterial
challenge. Stimulation of human monocytes with the Toll-like
receptor 4 (TLR4) ligand LPS and with IFN causes use of proximal
poly(A) sites in terminal exons that contain two or more poly(A)
sites to be favored. global shortening of 3-UTRs and a loss of key
regulatory elements such as miRNA target sites and AU rich elements
(AREs) Alternative splicing can alter the sequence of the encoded
protein as a result of: mutually exclusive exons exon skipping
intron retention alternative use of 5 or 3 splice sites at intron
ends Alternative promoter use alternative first exons in length and
sequence of the 5-UTR Alternative polyadenylation within an intron
mRNA encoding a truncated protein product Alternative
polyadenylation within the last exon shortening or extension the
3-UTR
Slide 14
Toll-like receptor (TLR) signaling pathways are regulated
through diverse transcripts generated by alternative splicing and
alternative polyadenylation Carpenter, S. et al. Nature Reviews
Immunol, 14, 361 (2014)
Slide 15
MicroRNA Regulation of the Immune System
Slide 16
Biogenesis and functional mechanisms of miRNAs, piRNAs and
snoRNAs Esteller, M. Nature Reviews Genetics 12, 861-874
(2011)
Slide 17
Regulation of miRNA-mediated gene repression by alternative
polyadenylation miRNAs regulate gene expression
post-transcriptionally by forming imperfect base pairing with
sequences in the 3 UTR of mRNAs, thereby reducing protein synthesis
by repression of translation or by inducing mRNA destabilization
and degradation. Alternative polyadenylation leads to mRNAs with
varying length of their 3UTR. Usage of different 3UTR lengths is a
way to allow or avoid miRNA-mediated repression. Lymphocyte
activation is associated with 3UTR shortening the same gene subject
to miRNA- mediated regulation when it has a long 3UTR is less
likely to be targeted by miRNAs once it shortens its 3 UTR. Jeker,
L.T. and J.A. Bluestone. Immunological Reviews 253, 65-81
(2013)
Slide 18
More than half of the miRNA-binding sites are downstream from
the first polyadenylation site, significant level of miRNA
regulation may be lost during T-cell proliferation. Genes whose
transcript expression increased during T-cell activation more
frequently contain miRNA-binding sites exclusively in their
extended 3 UTR than genes whose expression decreased, suggesting
that they were repressed by miRNAs before activation. Predicted
miR-155 and miR-17-92 target genes use the proximal polyadenylation
site more frequently than the distal one compared with non-targets
in stimulated T cells genes whose expression is needed but that are
targeted by the activation- induced miRNAs miR-155 and miR-17-92
may use the short form of their 3UTR to avoid repression during
activation, allowing one miRNA to exert differential functions in
resting and activated T cells Differential regulation of short
versus long 3 UTR usage by predicted miR-155 and miR-17-92 target
genes defines a subset of genes for repression while genes that
require neutral or induced expression will switch to using the
short 3UTR
Slide 19
Schematic representation of an extracellular cue (e.g.
cytokine) on a T cell and its consequence on the genetic network in
absence and presence of alternative polyadenylation (APA) (A) A
cytokine induces a network of genes A-M. (B) miRNA expression
allows to shape the gene expression program induced by the
cytokine. (C) The interplay of miRNA expression and APA provides a
cell additional flexibility to respond to the cytokine. Jeker, L.T.
and J.A. Bluestone. Immunological Reviews 253, 65-81 (2013)
Slide 20
Regulation of the TLR4 signaling pathway uses alternative
splicing of mRNAs encoding the receptor (TLR4) and the co-receptor
(MD2), the adaptor molecules (myeloid differentiation primary
response protein 88 (MYD88) and TRIF-related adaptor molecule
(TRAM), as well as the IL 1R associated kinases (IRAKs) AP 1,
activator protein 1; IRF, interferon-regulatory factor; LPS,
lipopolysaccharide; MD2B, splice variant of MD2; MYD88s, splice
variant of MYD88; NF B, nuclear factor B; smTLR4, soluble TLR4
splice variant; TAG, splice variant of TRAM; TRAF, TNF
receptor-associated factor; TRIF, TIR-domain- containing adaptor
protein inducing IFN Carpenter, S. et al. Nature Reviews Immunol,
14, 361 (2014) The use of shorter protein isoforms to fine-tune
signaling appears to be a common mechanism that occurs throughout
the TLR signaling pathway
Slide 21
T bet (encoded by Tbx21) is an immune cell-specific member of
the T box family of transcription factors that functions as a
master regulator of commitment to Th1 cell lineage and represents a
bridge between innate and adaptive immunity. Together with STAT4, T
bet has two central roles in the generation of transcriptionally
competent Th1 cell specific genes in CD4+ T cells. T bet-mediates
epigenetic changes that are primarily dependent on recruitment of
enzymes that generate chromatin modifications associated with
either gene activation (histone H3 or H4 acetylation, and H3 lysine
4 (H3K4) dimethylation) or gene repression (H3K27 trimethylation).
T bet also organizes the 3D architecture of the Ifng locus by
enhancing occupancy of the transcriptional repressor CCCTC-binding
factor (CTCF) between the boundaries of the Ifng locus and a +1 kb
site. This binding promotes CTCF-dependent chromatin looping, which
brings T bet-binding enhancers and CTCF-binding sites in close
proximity at the Ifng promoter Ifng expression in TH1 cells. T bet
expression in TH1 cells is fine-tuned post-transcriptionally by the
microRNA 29 cluster T-bet
Slide 22
Regulation by miRNAs in innate immunity In the immune system,
miRNAs have been shown to regulate lineage commitment,
proliferation, effector functions, and differentiation in normal
and diseased conditions. Activation of the innate immune response
with changes in expression of a number of selected miRNAs,
including miR-146, miR-155, miR-132, and miR-9. miR-146a is among
the most studied miRNAs, and is recognized as a modulator of
differentiation and function of cells of both innate and adaptive
immunity.
Slide 23
Regulation by miRNAs in innate immunity In the immune system,
miRNAs have been shown to regulate lineage commitment,
proliferation, effector functions, and differentiation in normal
and diseased conditions. Activation of the innate immune response
with changes in expression of a number of selected miRNAs,
including miR-146, miR-155, miR-132, and miR-9. miR-146a is among
the most studied miRNAs, and is recognized as a modulator of
differentiation and function of cells of both innate and adaptive
immunity. Both miR-155 and miR-146a are important regulators of
inflammation. Both are upregulated in response to LPS in monocytes,
but show opposing effects, with miR-155 enhancing and miR-146a
inhibiting inflammation. miR-146a is expressed throughout the
hematopoietic system. Its expression is low in precursors and
resting cells (with the exception of Treg cells) but increases with
maturation and activation. The role of miR-146a is to act as a
brake on the immune system (mice genetically ablated for miR146a
exhibit a significant immunoproliferative disorder and premature
death.
Slide 24
Regulation by miRNAs in innate immunity In the immune system,
miRNAs have been shown to regulate lineage commitment,
proliferation, effector functions, and differentiation in normal
and diseased conditions. Activation of the innate immune response
with changes in expression of a number of selected miRNAs,
including miR-146, miR-155, miR-132, and miR-9. miR-146a is among
the most studied miRNAs, and is recognized as a modulator of
differentiation and function of cells of both innate and adaptive
immunity. Both miR-155 and miR-146a are important regulators of
inflammation. Both are upregulated in response to LPS in monocytes,
but show opposing effects, with miR-155 enhancing and miR-146a
inhibiting inflammation. miR-146a is expressed throughout the
hematopoietic system. Its expression is low in precursors and
resting cells (with the exception of Treg cells) but increases with
maturation and activation. The role of miR-146a is to act as a
brake on the immune system (mice genetically ablated for miR146a
exhibit a significant immunoproliferative disorder and premature
death. Aging mice lacking miR-146a spontaneously developed tumors
in secondary lymphoid organs, pointing toward an essential role for
this miRNA in regulating development and activation of immune
cells. Originally identified in a screen for miRNAs induced by LPS
stimulation and shown to be a negative regulator of NF- B
signaling.
Slide 25
Induction of miR-146a upon stimulation of TLR4 leads to
negative regulation of NF- signaling Stimulation of macrophages or
mast cells with LPS leads to activation of the NF- B pathway with
nuclear translocation of NF- B, where it activates the expression
of specific genes, leading to a physiological response. Among the
genes transcriptionally induced by NF- B is also pri-miR-146a. NF-
B dependent up- regulation of miR-146a leads to reduced NF- B
activity through direct targeting of IRAK1 and TRAF6. Montagner, S.
et al. Immunological Reviews 253, 12-24 (2013)
Slide 26
Involvement of miRNAs in control of T cell development
Slide 27
Activated naive CD4+ T cells were untransduced () or transduced
(+) with a lentiviral vector encoding the precursor of miR-125b.
The maintenance of high level of miR-125b during naive CD4+ T cells
differentiation prevents the acquisition both of the effector
memory phenotype (cell membrane expression of the two cytokine
receptors IL-2Rb and IL-10Ra) and of effector functions
(intracellular accumulation of the cytokines IFN- and IL-13).
Enforcement of naive state in primary human lymphocytes by
miR-125b
Slide 28
Net importance of miRNAs in control of T cell development
T-cell differentiation and peripheral function is shown in
schematic form progressing from the thymic stages of double
negative (DN), double positive (DP), and CD4 and CD8 single
positive (SP) stages, including the tolerance checkpoints of
negative selection and regulatory T-cell (Treg) induction. The
proportional net importance of the global microRNA network, as
measured by the severity of the impact in Dicer-deficient cells, is
illustrated along the bottom of the schematic in red.
Slide 29
Regulation by miRNAs in adaptive immunity Expression profiles
of microRNA exhibit a dynamic pattern of regulation throughout
thymocyte differentiation. Functional analysis of
microRNA-deficient thymocytes reveals major differences depending
on when the ability to generate mature microRNA is lost.
Lck-Cre-mediated excision of Dicer early depletion of the microRNA
network 10-fold decline in thymic cellularity, with a defect in
differentiation past the DN stage.
Slide 30
Regulation by miRNAs in adaptive immunity Expression profiles
of microRNA exhibit a dynamic pattern of regulation throughout
thymocyte differentiation. Functional analysis of
microRNA-deficient thymocytes reveals major differences depending
on when the ability to generate mature microRNA is lost.
Lck-Cre-mediated excision of Dicer early depletion of the microRNA
network 10-fold decline in thymic cellularity, with a defect in
differentiation past the DN stage. Thymocyte differentiation past
the DN stage appears to be relatively intact in Lck-Cre-mediated
Dicer-deficient mice. Delaying Dicer-excision past the DN-DP
transition, Dicer-deficient thymocytes impeded progression from DP
to SP stages A major contributor to the function of microRNA during
positive selection is thought to be the miR-181 family, which may
constitute up to half of the total microRNA content of DP
cells.
Slide 31
Regulation by miRNAs in adaptive immunity Expression profiles
of microRNA exhibit a dynamic pattern of regulation throughout
thymocyte differentiation. Functional analysis of
microRNA-deficient thymocytes reveals major differences depending
on when the ability to generate mature microRNA is lost.
Lck-Cre-mediated excision of Dicer early depletion of the microRNA
network 10-fold decline in thymic cellularity, with a defect in
differentiation past the DN stage. Thymocyte differentiation past
the DN stage appears to be relatively intact in Lck-Cre-mediated
Dicer-deficient mice. Delaying Dicer-excision past the DN-DP
transition, Dicer-deficient thymocytes impeded progression from DP
to SP stages A major contributor to the function of microRNA during
positive selection is thought to be the miR-181 family, which may
constitute up to half of the total microRNA content of DP cells.
The function of elevated miR-181 in thymocytes may be both to aid
the positive selection off of weak ligands and to enhance
sensitivity to negative selection from strong ligands. miR-181 may
have functions in addition to adjusting TCR signal strength, such
as modulation of Notch signaling.
Slide 32
miRNA functions in CD4+ T-cell homeostasis, activation, and
effector polarization Key cellular events of peripheral CD4+ T
cells: maintenance of the naive T-cell pool through homeostasis,
proliferation, and activation upon antigen stimulation, and
polarization into effector lineages, including IFN -producing Th1
cells, IL-4-producing Th2 cells, and IL-17-producing Th17 cells.
The net contribution of the microRNA network to each stage is
indicated with either a red plus (indicating a positive effect) or
red minus (indicating a negative effect).
Slide 33
miRNA control in the differentiation of CD4+ T helper (Th) cell
subsets miRNAs regulate the differentation of different effector
(Th1, Th2, Th17, and (Tfh) and regulatory (Treg) subpopulations of
CD4+ T helper cells (miRNAs shown in green (red) are reported to
positively (negatively) regulate their differentiation). miRNAs
regulate the differentation of different effector (Th1, Th2, Th17,
and Tfh) and regulatory (Treg) subpopulations of CD4+ T helper
cells. miRNAs shown in green (red) are reported to positively
(negatively) regulate their differentiation.
Slide 34
Summary of the functions individual miRNAs play in T cells
Slide 35
Long ncRNA Regulation of the Immune System
Slide 36
Studies in macrophages have also revealed important roles for
lncRNAs in controlling inflammatory gene expression. Many lncRNAs
were found to be dynamically regulated in macrophages that were
exposed to TLR2 ligands. One such transcript, lincRNA Cox2, was
found to act as a master regulator of gene expression. Regulation
by lncRNAs in adaptive immunity
Slide 37
Studies in macrophages have also revealed important roles for
lncRNAs in controlling inflammatory gene expression. Many lncRNAs
were found to be dynamically regulated in macrophages that were
exposed to TLR2 ligands. One such transcript, lincRNA Cox2, was
found to act as a master regulator of gene expression. lincRNA Cox2
represses the basal expression of IFN-stimulated genes (ISGs) by
partnering with the heterogeneous nuclear ribonucleoproteins
(hnRNPs) hnRNPA/B and hnRNPA2/B1. lincRNA Cox2 is also essential
for the TLR-induced expression of il6 and more than 700 additional
genes (many of which are secondary immune response genes). A
pseudogene RNA named Lethe binds RELA (the p65 subunit of NF B
heterodimeric complex), which prevents NF B from binding to
promoter regions of target genes. In addition, a lincRNA called TNF
and hnRNPL-related immunoregulatory lincRNA (THRIL) has been shown
to regulate the expression of tumour necrosis factor (TNF) in human
monocytes through its interactions with hnRNPL. Regulation by
lncRNAs in adaptive immunity
Slide 38
Regulation of inflammatory gene expression by lincRNA-Cox2
Slide 39
The lncRNA Tmevpg1 (a.k.a. NeST) controls Theilers virus
persistence in mice by promoting the transcription of Ifng in CD8+
T cells. The Tmevpg1 lncRNA binds to WD repeat-containing protein 5
(WDR5), a histone-modifying complex, altering histone 3 (H3) lysine
4 trimethylation at the Ifng locus.. Regulation by lncRNAs in
adaptive immunity
Slide 40
The lncRNA Tmevpg1 (a.k.a. NeST) controls Theilers virus
persistence in mice by promoting the transcription of Ifng in CD8+
T cells. The Tmevpg1 lncRNA binds to WD repeat-containing protein 5
(WDR5), a histone-modifying complex, altering histone 3 (H3) lysine
4 trimethylation at the Ifng locus.. lncRNA DQ786243 affects Treg
related cAMP response element binding protein (CREB) and Foxp3
expression in Crohns disease. CREB is important for the activity of
the TCR response element in the Foxp3 (forkhead box P3, a master
transcription factor in function and development of Treg cells).
CD4 T cell activation requires low levels of intracellular cAMP,
which plays an important role in contact-dependent manner to
control the suppressive function of nTreg cells. This finding may
provide a interrelationship between a lncRNA (DQ786243 )and a miRNA
(miR-142-3p) in immune regulation. Regulation by lncRNAs in
adaptive immunity
Slide 41
nTreg contains much higher levels of cAMP than do nave or
effector CD4 T cells. nTreg releases intracellular cAMP into
effector T cells suppression of effector cell function. Activated
helper CD4 T cell contains high levels of PDE, which is
down-regulated in the nTreg. Blocking of cAMP degradation by PDE4
inhibitor leads to increased Tregs suppressive function. Elevated
levels of intracellular cAMP blocks IL-12 signaling pathway in
target cells and thus suppress its differentiation into Th1
lineage. Down-regulation of miR142-3p is essential for Treg
function. miR-142-3p maintains low levels of intracellular cAMP by
targeting adenylyl cyclase (AC) 9 mRNA. In Treg cells, Foxp3
directly down-regulates miR-142-3p expression and keeps the
AC9/cAMP pathway active, elevates intracellular cAMP levels, and
down-regulates miR142-3p required for suppressor function of Treg
cells. Possible interrelationship between lncRNAs and miRNAs in
adaptive immunity
Slide 42
Expression of CD4 or CD8 defines two distinct T-cell lineages
that differ both by their MHC specificity and by their function.
CD4+ T cells are MHC class II restricted and function as T helper
(Th) cells when activated, assisting effector components of the
immune system (such as B cells) through cytokine secretion and
upregulation of expression of specific membrane ligands. CD8+ T
cells are MHC class I restricted and after activation, acquire
cytotoxic properties that allow them to directly kill cells
expressing their target antigen. Given that CD4+ and CD8+ T cells
are derived from a common precursor pool of DP thymocytes, two
interesting questions are: Which signals direct thymocytes to
either lineage? What are the cytosolic intermediates and nuclear
effectors that transform these signals into CD4- or CD8-specific
gene-expression programs? It is an intriguing possibility that one
or more lncRNAs might be involved in directing this lineage
commitment through a mechanism similar to that utilized in XCI,
genetic imprinting, or mating-type switching in budding yeast.
Slide 43
Additional references can be provided on ncRNAs, the immune
system, autoimmunity, and other immunological disorders if anyone
is interested