Décisions épigénétiques et reproduction chez les mammifères

Publications

Année de publication : 2006

Timothy H Bestor, Déborah Bourc'his (2006 Feb 28)

Genetics and epigenetics of hydatidiform moles.

Nature genetics : 274-6 En savoir plus
Résumé

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Année de publication : 2005

Jie Liu, Min Chen, Chuxia Deng, Déborah Bourc'his, Julie G Nealon, Beth Erlichman, Timothy H Bestor, Lee S Weinstein (2005 Apr 7)

Identification of the control region for tissue-specific imprinting of the stimulatory G protein alpha-subunit.

Proceedings of the National Academy of Sciences of the United States of America : 5513-8 En savoir plus
Résumé

Gnas is a complex gene with multiple imprinted promoters. The upstream Nesp and Nespas/Gnasxl promoters are paternally and maternally methylated, respectively. The downstream promoter for the stimulatory G protein alpha-subunit (G(s)alpha) is unmethylated, although in some tissues (e.g., renal proximal tubules), G(s)alpha is poorly expressed from the paternal allele. Just upstream of the G(s)alpha promoter is a primary imprint mark (1A region) where maternal-specific methylation is established during oogenesis. Pseudohypoparathyroidism type 1B, a disorder of renal parathyroid hormone resistance, is associated with loss of 1A methylation. Analysis of embryos of Dnmt3L(-/-) mothers (which cannot methylate maternal imprint marks) showed that Nesp, Nespas/Gnasxl, and 1A imprinting depend on one or more maternal primary imprint marks. We generated mice with deletion of the 1A differentially methylated region. These mice had normal Nesp-Nespas/Gnasxl imprinting, indicating that the Gnas locus contains two independent imprinting domains (Nespas-Nespas/Gnasxl and 1A-G(s)alpha) controlled by distinct maternal primary imprint marks. Paternal, but not maternal, 1A deletion resulted in G(s)alpha overexpression in proximal tubules and evidence for increased parathyroid hormone sensitivity but had no effect on G(s)alpha expression in other tissues where G(s)alpha is normally not imprinted. The 1A region is a maternal imprint mark that contains one or more methylation-sensitive cis-acting elements that suppress G(s)alpha expression from the paternal allele in a tissue-specific manner.

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Année de publication : 2004

Y L Jiang, M Rigolet, D Bourc'his, F Nigon, I Bokesoy, J P Fryns, M Hultén, P Jonveaux, P Maraschio, A Mégarbané, A Moncla, E Viegas-Péquignot (2004 Dec 8)

DNMT3B mutations and DNA methylation defect define two types of ICF syndrome.

Human mutation : 56-63 En savoir plus
Résumé

ICF syndrome is a rare autosomal recessive disease characterized by variable immunodeficiency, centromeric instability, and facial abnormalities. Mutations in the catalytic domain of DNMT3B, a gene encoding a de novo DNA methyltransferase, have been recognized in a subset of patients. ICF syndrome is a genetic disease directly related to a genomic methylation defect that mainly affects classical satellites 2 and 3, both components of constitutive heterochromatin. The variable incidence of DNMT3B mutations and the differential methylation defect of alpha satellites allow the identification of two types of patients, both showing an undermethylation of classical satellite DNA. This classification illustrates the specificity of the methylation process and raises questions about the genetic heterogeneity of the ICF syndrome.

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Déborah Bourc'his, Timothy H Bestor (2004 Aug 20)

Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L.

Nature : 96-9 En savoir plus
Résumé

Mammalian genomes employ heritable cytosine methylation in the long-term silencing of retrotransposons and genes subject to genomic imprinting and X chromosome inactivation. Little is known of the mechanisms that direct cytosine methylation to specific sequences. Here we show that DNA methyltransferase 3-like (Dnmt3L (ref. 1)) is expressed in testes during a brief perinatal period in the non-dividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation. Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes. Loss of Dnmt3L from early germ cells also caused meiotic failure in spermatocytes, which do not express Dnmt3L. Whereas dispersed repeated sequences were demethylated in mutant germ cells, tandem repeats in pericentric regions were methylated normally. This result indicates that the Dnmt3L protein might have a function in the de novo methylation of dispersed repeated sequences in a premeiotic genome scanning process that occurs in male germ cells at about the time of birth.

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