Décisions épigénétiques et reproduction chez les mammifères

Publications

Année de publication : 2008

Angélique Galvani, Déborah Bourc'his (2008 May 10)

[Heritable epimutations: a case study in humans].

Médecine sciences : M/S : 473-4 : DOI : 10.1051/medsci/2008245473 En savoir plus
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Andrew J Wood, Reiner Schulz, Kathryn Woodfine, Katarzyna Koltowska, Colin V Beechey, Jo Peters, Deborah Bourc'his, Rebecca J Oakey (2008 May 3)

Regulation of alternative polyadenylation by genomic imprinting.

Genes & development : 1141-6 : DOI : 10.1101/gad.473408 En savoir plus
Résumé

Maternally and paternally derived alleles can utilize different promoters, but allele-specific differences in cotranscriptional processes have not been reported. We show that alternative polyadenylation sites at a novel murine imprinted gene (H13) are utilized in an allele-specific manner. A differentially methylated CpG island separates polyA sites utilized on maternal and paternal alleles, and contains an internal promoter. Two genetic systems show that alleles lacking methylation generate truncated H13 transcripts that undergo internal polyadenylation. On methylated alleles, the internal promoter is inactive and elongation proceeds to downstream polyadenylation sites. This demonstrates that epigenetic modifications can influence utilization of alternative polyadenylation sites.

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Alexei A Aravin, Déborah Bourc'his (2008 Apr 17)

Small RNA guides for de novo DNA methylation in mammalian germ cells.

Genes & development : 970-5 : DOI : 10.1101/gad.1669408 En savoir plus
Résumé

Germline genomic methylation is essential for gamete identity and integrity in mammals. The study by Kuramochi-Miyagawa and colleagues (908-917) in the previous issue of Genes & Development links the process of DNA methylation-dependent repression of retrotranspons with the presence of piwi-interacting RNAs (piRNAs) in fetal male germ cells undergoing de novo methylation.

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Reiner Schulz, Kathryn Woodfine, Trevelyan R Menheniott, Deborah Bourc'his, Timothy Bestor, Rebecca J Oakey (2008 Apr 10)

WAMIDEX: a web atlas of murine genomic imprinting and differential expression.

Epigenetics : 89-96 En savoir plus
Résumé

The mouse is an established model organism for the study of genomic imprinting. Mice with genetic material originating from only one parent (e.g., mice with uniparental chromosomal duplications) or gene mutations leading to epigenetic deficiencies have proven to be particularly useful tools. In the process of our studies we have accumulated a large set of expression microarray measurements in samples derived from these types of mice. Here, we present the collation of these and third-party microarray data that are relevant to genomic imprinting into a Web Atlas of Murine genomic Imprinting and Differential EXpression (WAMIDEX: https://atlas.genetics.kcl.ac.uk). WAMIDEX integrates the most comprehensive literature-derived catalog of murine imprinted genes to date with a genome browser that makes the microarray data immediately accessible in annotation-rich genomic context. In addition, WAMIDEX exemplifies the use of the self-organizing map method for the discovery of novel imprinted genes from microarray data. The parent-of-origin-specific expression of imprinted genes is frequently limited to specific tissues or developmental stages, a fact that the atlas reflects in its design and data content.

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Déborah Bourc'his, Charlotte Proudhon (2008 Jan 8)

Sexual dimorphism in parental imprint ontogeny and contribution to embryonic development.

Molecular and cellular endocrinology : 87-94 : DOI : 10.1016/j.mce.2007.11.025 En savoir plus
Résumé

Genomic imprinting refers to the functional non-equivalence of parental genomes in mammals that results from the parent-of-origin allelic expression of a subset of genes. Parent-specific expression is dependent on the germ line acquisition of DNA methylation marks at imprinting control regions (ICRs), coordinated by the DNA-methyltransferase homolog DNMT3L. We discuss here how the gender-specific stages of DNMT3L expression may have influenced the various sexually dimorphic aspects of genomic imprinting: (1) the differential developmental timing of methylation establishment at paternally and maternally imprinted genes in each parental germ line, (2) the differential dependence on DNMT3L of parental methylation imprint establishment, (3) the unequal duration of paternal versus maternal methylation imprints during germ cell development, (4) the biased distribution of methylation-dependent ICRs towards the maternal genome, (5) the different genomic organization of paternal versus maternal ICRs, and finally (6) the overwhelming contribution of maternal germ line imprints to development compared to their paternal counterparts.

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Année de publication : 2007

Andrew J Wood, Déborah Bourc'his, Timothy H Bestor, Rebecca J Oakey (2007 Oct 19)

Allele-specific demethylation at an imprinted mammalian promoter.

Nucleic acids research : 7031-9 En savoir plus
Résumé

A screen for imprinted genes on mouse Chromosome 7 recently identified Inpp5f_v2, a paternally expressed retrogene lying within an intron of Inpp5f. Here, we identify a novel paternally expressed variant of the Inpp5f gene (Inpp5f_v3) that shows a number of unusual features. Inpp5f_v3 initiates from a CpG-rich repeat region adjoining two B1 elements, despite previous reports that SINEs are generally excluded from imprinted promoters. Accordingly, we find that the Inpp5f_v3 promoter acquires methylation around the time of implantation, when many repeat families undergo de novo epigenetic silencing. Methylation is then lost specifically on the paternally derived allele during the latter stages of embryonic development, resulting in imprinted transcriptional activation on the demethylated allele. Methylation analyses in embryos lacking maternal methylation imprints suggest that the primary imprinting mark resides within an intronic CpG island approximately 1 kb downstream of the Inpp5f_v3 transcriptional start site. These data support the hypothesis that SINEs can influence gene expression by attracting de novo methylation during development, a property likely to explain their exclusion from other imprinted promoters.

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Mounia Guenatri, Déborah Bourc'his (2007 Jul 17)

[In vitro methods of male germ cell specification and differentiation].

Médecine sciences : M/S : 619-25 En savoir plus
Résumé

Germ line specification is an early cell fate decision essential for the transmission of totipotency over generations. Two types of germ line stem cells populate the male gonads in mammals. Primordial germ cells (PGCs) are the germ line founders only present during prenatal life. Spermatogonial stem cells (SSCs) appear a few days after birth and divide asymmetrically to give rise to one stem cell and one spermatogonia that initiates differentiation to produce spermatozoa. Germ cell specification and differentiation involve specific environmental stimuli and a sequential order of maturing phases required for gamete function. Spatio-temporal controls similarly dictate the erasure of somatic methylation marks and the subsequent acquisition of sex-specific marks at imprinted genes in gametes. We review here the recent advancements in male germ cell derivation from ES cells and discuss the limits of these in vitro methods in providing a kinetics and a microenvironment suitable for the programming of a proper gametic and parental identity.

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Christopher B Schaefer, Steen K T Ooi, Timothy H Bestor, Déborah Bourc'his (2007 Apr 21)

Epigenetic decisions in mammalian germ cells.

Science (New York, N.Y.) : 398-9 En savoir plus
Résumé

Specific sequences are designated for de novo DNA methylation at CpG dinucleotides in mammalian germ cells. The result is the long-term transcriptional silencing of the methylated sequences, most of which are retrotransposons and CpG-rich sequences associated with imprinted genes. There is profound sexual dimorphism in both the nature of the sequences that undergo de novo methylation in germ cells and in the mechanism by which de novo methylation is regulated. The restriction of future gene expression by the imposition of heritable methylation patterns in germ cell genomes is characteristic of mammals but is rare in other taxa.

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Diana Lucifero, Sophie La Salle, Déborah Bourc'his, Josée Martel, Timothy H Bestor, Jacquetta M Trasler (2007 Apr 21)

Coordinate regulation of DNA methyltransferase expression during oogenesis.

BMC developmental biology : 36 En savoir plus
Résumé

Normal mammalian development requires the action of DNA methyltransferases (DNMTs) for the establishment and maintenance of DNA methylation within repeat elements and imprinted genes. Here we report the expression dynamics of Dnmt3a and Dnmt3b, as well as a regulator of DNA methylation, Dnmt3L, in isolated female germ cells.

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Michelle A Carmell, Angélique Girard, Henk J G van de Kant, Deborah Bourc'his, Timothy H Bestor, Dirk G de Rooij, Gregory J Hannon (2007 Mar 31)

MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline.

Developmental cell : 503-14 En savoir plus
Résumé

Small RNAs associate with Argonaute proteins and serve as sequence-specific guides for regulation of mRNA stability, productive translation, chromatin organization, and genome structure. In animals, the Argonaute superfamily segregates into two clades. The Argonaute clade acts in RNAi and in microRNA-mediated gene regulation in partnership with 21-22 nt RNAs. The Piwi clade, and their 26-30 nt piRNA partners, have yet to be assigned definitive functions. In mice, two Piwi-family members have been demonstrated to have essential roles in spermatogenesis. Here, we examine the effects of disrupting the gene encoding the third family member, MIWI2. Miwi2-deficient mice display a meiotic-progression defect in early prophase of meiosis I and a marked and progressive loss of germ cells with age. These phenotypes may be linked to an inappropriate activation of transposable elements detected in Miwi2 mutants. Our observations suggest a conserved function for Piwi-clade proteins in the control of transposons in the germline.

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Année de publication : 2006

T C Shovlin, D Bourc'his, S La Salle, A O'Doherty, J M Trasler, T H Bestor, C P Walsh (2006 Oct 25)

Sex-specific promoters regulate Dnmt3L expression in mouse germ cells.

Human reproduction (Oxford, England) : 457-67 En savoir plus
Résumé

Dnmt3L, a member of the DNA methyltransferase 3 family, lacks enzymatic activity but is required for de-novo methylation of imprinted genes in oocytes and for transposon repression in male germ cells.

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D Bourc'his, T H Bestor (2006 Apr 1)

Origins of extreme sexual dimorphism in genomic imprinting.

Cytogenetic and genome research : 36-40 En savoir plus
Résumé

Roughly equal numbers of imprinted genes are subject to repression from alleles of maternal and of paternal origin. This masks the strong sexual dimorphism that underlies major aspects of imprinted gene regulation. First, imprints are established very early in the male germ line and persist for the reproductive life of the organism, while maternal genomic imprints are established shortly prior to ovulation and are erased soon thereafter in the primordial germ cells of the next generation. Second, many CpG island-associated promoters are subject to maternal methylation but no known promoters are subject to paternal-specific germline methylation. The few known paternal methylation marks are kilobases distant from the affected genes and have a low CpG density. Third, Dnmt3L is required for imprint establishment but not transposon methylation in female germ cells, while Dnmt3L is required for transposon methylation and has only a minor role in de novo methylation at imprinted loci in male germ cells. Fourth, maternally expressed genes are commonly repressed on the paternal allele by paternally expressed imprinted genes produced in cis and encoding nontranslated RNAs. It is here suggested that rapid loss of highly mutable methylated CpG sites has led to the depletion of methylation target sites in paternally repressed imprinted genes, and that an imprinting mechanism based on RNAs or local inhibitory influences of ongoing transcription of regulatory loci has evolved to counter the erosion of paternally methylated regulatory regions. This mutability model is based on the fact that paternally methylated sequences are maintained in the methylated state for a much longer time than are maternally methylated sequences, and are therefore lost at a correspondingly faster rate. The difference in timing of imprint establishment is likely to underlie the increasing sexual dimorphism of other aspects of imprinted gene expression.

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

Genetics and epigenetics of hydatidiform moles.

Nature genetics : 274-6 En savoir plus
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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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