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Biology 2014, 3(3), 578-605; doi:10.3390/biology3030578

Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases

CNRS UMR7216, Epigenetics and Cell Fate, Université Paris Diderot, Bâtiment Lamarck, 4ème étage Case Courrier 7042, 35 rue Hélène Brion, 75205 Paris, France
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Received: 18 May 2014 / Revised: 18 July 2014 / Accepted: 21 August 2014 / Published: 5 September 2014
(This article belongs to the Special Issue DNA Methylation)
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Abstract

The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes. View Full-Text
Keywords: DNA methylation; DNMT3B; germ line genes; centromeric repeats; ICF syndrome; cancer DNA methylation; DNMT3B; germ line genes; centromeric repeats; ICF syndrome; cancer
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MDPI and ACS Style

Walton, E.L.; Francastel, C.; Velasco, G. Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases. Biology 2014, 3, 578-605.

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