DNA methylation and genome maintenance

When studying a rare disease sheds new light on the field of DNA methylation

Mutation in the 4 four genes induces centromeres hypomethylation

DNA methylation is among the best-studied epigenetic modification in vertebrates and is essential for normal embryonic development. Given its pivotal role in the control of gene expression and key biological processes, it comes as no surprise that perturbed DNA methylation patterns are hallmarks of many human diseases. In this context, the DNA methylation machinery is frequently perturbed although the causal link is sometimes difficult to formally establish. However, inherited monogenic disorders that disrupt components of the epigenetic machinery offer a unique opportunity to learn about (epi)genome maintenance.

Our interest in the transcription of repeated sequences has motivated our interest in a rare autosomal recessive disease, the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies), caused by the remarkable loss of DNA methylation at (peri)centromeric repeats that cause chromosomal instability. Mutations in the DNA methyltransferase DNMT3B were the first reported causes of the disease. The study of its etiology has recently fuelled the field with new candidate players, whose role in DNA methylation and maintenance of genome stability had never been suspected before their implication in the disease.

This raised important questions regarding their function, their direct or indirect role in pathways to DNA methylation, their genomic targets and the impact of their mutations on transcriptome, epigenome and cell fate. We aim at providing a comprehensive and integrated view of the consequences of perturbed DNA methylation in cells from patients and mouse models with important consequences to (i) understand the genotype/phenotype relationship in such a complex monogenic and epigenetic disease, (ii) establish biomarkers to aid diagnosis and prioritize patients for mutation screening and appropriate management, and (iii) in a more basic research orientation, to shed new light on the molecular mechanisms involved in establishment and maintenance of DNA methylation patterns at DNA repeats and unique genes, and on the consequences for long and short, coding and non-coding transcriptional output, with added relevance to other physiopathological contexts.

Related publications:

Gatto S, Gagliardi M, Franzese M, Leppert S, Papa M, Cammisa M, Grillo G, Velasco G, Francastel C, Toubiana S, D’Esposito M, Angelini C, Matarazzo MR. ICF-specific DNMT3B dysfunction interferes with intragenic regulation of mRNA transcription and alternative splicing . Nucleic Acids Res. 2017 Mar 9; 45(10):5739-5756. PMID: 28334849
Sagie S, Toubiana S, Hartono S, Katzir H, Tzur-Gilat A, Havazelet S, Francastel C, Velasco G, Chedin F, Selig S. Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids. Nat Commun. 2017 Jan 24;8:14015. PMID: 28117327
Sterlin D, Velasco G, Moshous D, Touzot F, Mahlaoui N, Fischer A, Suarez F, Francastel C, Picard C. Genetic, Cellular and Clinical Features of ICF Syndrome: a French National Survey . J Clin Immunol. 2016 Feb;36(2):149-59. PMID: 26851945
Thijssen PE, Ito Y, Grillo G, Wang J, Velasco G, Nitta H, Unoki M, Yoshihara M, Suyama M, Sun Y, Lemmers RJ, de Greef JC, Gennery A, Picco P, Kloeckener-Gruissem B, Güngör T, Reisli I, Picard C, Kebaili K, Roquelaure B, Iwai T, Kondo I, Kubota T, van Ostaijen-Ten Dam MM, van Tol MJ, Weemaes C, Francastel C, van der Maarel SM, Sasaki H. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun. 2015 Jul 28;6:7870. PMID: 26216346
Walton E, Francastel C, Velasco G. Dnmt3b prefers germ line genes and centromeric regions: lessons from ICF and cancer and implications for diseases. Biology (Basel). 2014 Sep 5;3(3):578-605. PMID: 25198254
Velasco G, Walton EL, Sterlin D, Hédouin S, Nitta H, Yuya I, Fouyssac F, Mégarbané A, Sasaki H, Picard C, Francastel C. Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology. Orphanet J Rare Dis. 2014 Apr 17;9(1):56. PMID: 24742017
Nitta H, Unoki M, Ichiyanagi K, Kosho T, Shigemura T, Takahashi H, Velasco G, Francastel C, Picard C, Kubota T, Sasaki H. Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. J Hum Genet. 2013 Jul;58(7):455-60. PMID: 23739126
Walton EL, Francastel C, Velasco G. Maintenance of DNA methylation: Dnmt3b joins the dance. Epigenetics. 2011 Nov;6(11):1373-7. PMID: 22048250
Velasco G, Hubé F, Rollin J, Neuillet D, Philippe C, Bouzinba-Segard H, Galvani A, Viegas-Péquignot E, Francastel C. Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9281-6. PMID: 20439742

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