CTCF and CTCF and Imprinting Imprinting DisorderDisorder

Preeti MisraSang-Gook

Han

Contents

•Gene Network

•Epigenetic - Acetylation - Methylation

•Properties of CTCF

•Pathway - CTCF

•Human diseases

Background Interesting Protein and Diseases

•Loss of Imprinting

Background: Gene Network

• Activation and Inhibition with evolution

Control: Achieve an objective of the system

Survival, reproduction

P(t)

H(t)

+U(t) Y(t)

-

+C(t)

Background: EpigeneticEpigenetic : Surface of genetic Gene expression control without modification of

DNA sequence.

Histone Modification–Acetylation–Methylation

DNA Methylation - Methylation of Cystosine(C). - CpG island

Expansion Condensation

Background: Epigenetic

DNA Methylation

• Post-synthetic modifications of Chromatin structure

• Cytosine-Guanine (CG) base pair is methylated.

• Regulation in gene expression.

Background: Loss of epigenetic marks.

Background: Genomic Imprinting

DMR: Differentially Methylated RegionICR: Imprinting Control Region

father

mother

CTCF Protein

• Gene location: 16q22• 11 zinc fingers.• Transcription Binding Factor : (MYC, PLK, PIM-1, p19ARF, and

Igf2/H19, APPβ,β-globin, and lysozyme regulatory sequences )

• Binding to TFBSs including ICR and CpG island.• Cis-regulartory.• Regulation of DNA methylation pattern• Highly conserved.• There are 39,622 ZnFg registered in pFam

CTCF motif

CTCF Structure Classification and GO

C - x(2,4) - C - x(3) - [LIVMFYWC] - x(8) - H - x(3,5) – HGSSGSSGRTHTGEKPYACSHCDKTFRQKQLLDMHFKRYHDPNFVPAAFVCSKCGKTFTRRNTMARHADNCAGPDGVEGENSGPSSG

CTCF Protein : C2H2 type

CTCF and its Uses

• CTCF is involved in the control of cell growth and differentiation. • Involved in IGF2 imprinting regulation.

• CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function“.

• CTCF may establishes a regulatable epigenetic switch for X-inactivation

Human Disease: Beckwith-Wiedemann

syndromeBWS locus: 11p15.5

BWS occurs in 1:13,700

Phenotypes:

1. Macroglossia:

Problem with Eating, Breathing, speaking

2. Abdominal wall defects

3. Fast growth:

birth weight and height (above mean)

enlarge internal organs (kidneys, liver,pancreas)

hemihyperplasia

4. Ear lobe

Pathway : BWS

CTCF Inhibit the enhancer from activating IGF2(Insulin-like Growth Factor 2) and causes H19 to be expressed.

Wilms’ Tumor BWS Tumor

Mutation

ZF3 ZF3 ZF3 ZF7

Other Diseases • Prader-Willis Syndrome(PWS)-failure to thrive during infancy and hyperphagia.

• Angelman syndrome(AS)- mental retardation and speech impairment

• Transient neonatal diabetes mellitis(TNDM)-a rare form of

diabetes

• Alpha-thalassemiaoccurs(males)- mental retardation syndrome.

Capta

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Reference• http://www.benbest.com/health/cancer.html

• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=10664

• Marcus Vinicius de Matos Gomes; Ester Silveira Ramos (2003), Beckwith-Wiedemann syndrome and isolated hemihyperplasia, Sao Paulo Med J. 21, 133-138

• Keith D. Robertson (2004), DNA Methylation and Human Disease, Nature, 6, 597-610

• Galina N. Filippova, et. al. (2002), Tumor-associated Zinc Finger Mutations in the CTCF Transcription Factor Selectively Alter Its DNA-binding Specificity, Cancer Research, 62, 48-52

Question Time!!!!