Allele-specific Methylation of a Functional CTCF Binding Site Upstream of MEG3 in the Human Imprinted Domain of 14q32

Overview

Journal Chromosome Res

Date 2005 Dec 7

PMID 16331412

Citations 23

Authors

Alberto L Rosa

Yuan-Qing Wu

Bernard Kwabi-Addo

Karen J Coveler

V Reid Sutton

Lisa G Shaffer

Affiliations

Soon will be listed here.

Abstract

The gene MEG3 is located in the imprinted human chromosomal region on 14q32. Imprinting of a structurally homologous region IGF2/H19 on 11p15 is mediated through cytosine methylation-controlled binding of the protein CTCF to target sites upstream of H19. We identified five new CTCF binding sites around the promoter of MEG3. Using an electrophoretic mobility shift assay, we showed that these sites bind CTCF in vitro. Using one of these sites, chromatin immunoprecipitation (ChIP) analysis confirmed CTCF binding in-vivo, and differential allele-specific methylation was demonstrated in seven individuals with either maternal or paternal uniparental disomy 14 (UPD14). The site was unmethylated on the maternally inherited chromosomes 14 and methylated on the paternally inherited chromosomes 14, suggesting parent-specific methylation of sequences upstream of MEG3. We speculate that this CTCF-binding region may provide a mechanism for the transcriptional regulation of MEG3 and DLK1.

Citing Articles

The long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation.

Farhadova S, Ghousein A, Charon F, Surcis C, Gomez-Velazques M, Roidor C Nucleic Acids Res. 2024; 52(11):6183-6200.

PMID: 38613389 PMC: 11194098. DOI: 10.1093/nar/gkae247.

The multifaceted biology of lncR-Meg3 in cardio-cerebrovascular diseases.

Li J, Liu W, Peng F, Cao X, Xie X, Peng C Front Genet. 2023; 14:1132884.

PMID: 36968595 PMC: 10036404. DOI: 10.3389/fgene.2023.1132884.

Deletion of -DMR Enhances Migration and Invasion of MLTC-1 Depending on the CTCF Binding Sites.

Han X, He H, Shao L, Cui S, Yu H, Zhang X Int J Mol Sci. 2022; 23(15).

PMID: 35955961 PMC: 9369160. DOI: 10.3390/ijms23158828.

Essential Role of the 14q32 Encoded miRNAs in Endocrine Tumors.

Krokker L, Patocs A, Butz H Genes (Basel). 2021; 12(5).

PMID: 34066712 PMC: 8151414. DOI: 10.3390/genes12050698.

CTCF modulates allele-specific sub-TAD organization and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains.

Lleres D, Moindrot B, Pathak R, Piras V, Matelot M, Pignard B Genome Biol. 2019; 20(1):272.

PMID: 31831055 PMC: 6909504. DOI: 10.1186/s13059-019-1896-8.

References

Szabo P, Tang S, Silva F, Tsark W, Mann J . Role of CTCF binding sites in the Igf2/H19 imprinting control region. Mol Cell Biol. 2004; 24(11):4791-800. PMC: 416431. DOI: 10.1128/MCB.24.11.4791-4800.2004. View

Wolffe A . Transcriptional control: imprinting insulation. Curr Biol. 2000; 10(12):R463-5. DOI: 10.1016/s0960-9822(00)00534-0. View

Filippova G, Thienes C, Penn B, Cho D, Hu Y, Moore J . CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet. 2001; 28(4):335-43. DOI: 10.1038/ng570. View

Sutton V, Coveler K, Lalani S, Kashork C, Shaffer L . Subtelomeric FISH uncovers trisomy 14q32: lessons for imprinted regions, cryptic rearrangements and variant acrocentric short arms. Am J Med Genet. 2002; 112(1):23-7. DOI: 10.1002/ajmg.10703. View

Sasaki H, Ishihara K, Kato R . Mechanisms of Igf2/H19 imprinting: DNA methylation, chromatin and long-distance gene regulation. J Biochem. 2000; 127(5):711-5. DOI: 10.1093/oxfordjournals.jbchem.a022661. View

Bell A, West A, Felsenfeld G . The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999; 98(3):387-96. DOI: 10.1016/s0092-8674(00)81967-4. View

Zhang X, Zhou Y, Mehta K, Danila D, Scolavino S, Johnson S . A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab. 2003; 88(11):5119-26. DOI: 10.1210/jc.2003-030222. View

Kobayashi S, Wagatsuma H, Ono R, Ichikawa H, Yamazaki M, Tashiro H . Mouse Peg9/Dlk1 and human PEG9/DLK1 are paternally expressed imprinted genes closely located to the maternally expressed imprinted genes: mouse Meg3/Gtl2 and human MEG3. Genes Cells. 2001; 5(12):1029-37. DOI: 10.1046/j.1365-2443.2000.00390.x. View

Yu W, Ginjala V, Pant V, Chernukhin I, Whitehead J, Docquier F . Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat Genet. 2004; 36(10):1105-10. DOI: 10.1038/ng1426. View

10.

Pentao L, Lewis R, Ledbetter D, Patel P, Lupski J . Maternal uniparental isodisomy of chromosome 14: association with autosomal recessive rod monochromacy. Am J Hum Genet. 1992; 50(4):690-9. PMC: 1682625. View

11.

Charlier C, Segers K, Karim L, Shay T, Gyapay G, Cockett N . The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status. Nat Genet. 2001; 27(4):367-9. DOI: 10.1038/86856. View

12.

Walter C, Shaffer L, Kaye C, Huff R, Ghidoni P, McCaskill C . Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45,XY,idic(14)(p11). Am J Med Genet. 1996; 65(4):259-65. DOI: 10.1002/(SICI)1096-8628(19961111)65:4<259::AID-AJMG2>3.0.CO;2-K. View

13.

Morison I, Reeve A . A catalogue of imprinted genes and parent-of-origin effects in humans and animals. Hum Mol Genet. 1998; 7(10):1599-609. DOI: 10.1093/hmg/7.10.1599. View

14.

Wylie A, Murphy S, Orton T, Jirtle R . Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation. Genome Res. 2000; 10(11):1711-8. PMC: 310985. DOI: 10.1101/gr.161600. View

15.

Zimarino V, Wu C . Induction of sequence-specific binding of Drosophila heat shock activator protein without protein synthesis. Nature. 1987; 327(6124):727-30. DOI: 10.1038/327727a0. View

16.

Kanduri C, Pant V, Loukinov D, Pugacheva E, Qi C, Wolffe A . Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol. 2000; 10(14):853-6. DOI: 10.1016/s0960-9822(00)00597-2. View

17.

Ohlsson R, Renkawitz R, Lobanenkov V . CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 2001; 17(9):520-7. DOI: 10.1016/s0168-9525(01)02366-6. View

18.

Antonarakis S, Blouin J, Maher J, Avramopoulos D, Thomas G, Talbot Jr C . Maternal uniparental disomy for human chromosome 14, due to loss of a chromosome 14 from somatic cells with t(13;14) trisomy 14. Am J Hum Genet. 1993; 52(6):1145-52. PMC: 1682257. View

19.

Miyoshi N, Wagatsuma H, Wakana S, Shiroishi T, Nomura M, Aisaka K . Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells. 2000; 5(3):211-20. DOI: 10.1046/j.1365-2443.2000.00320.x. View

20.

Paulsen M, Takada S, Youngson N, Benchaib M, Charlier C, Segers K . Comparative sequence analysis of the imprinted Dlk1-Gtl2 locus in three mammalian species reveals highly conserved genomic elements and refines comparison with the Igf2-H19 region. Genome Res. 2001; 11(12):2085-94. PMC: 311216. DOI: 10.1101/gr.206901. View