Décisions épigénétiques et reproduction chez les mammifères

Publications

Année de publication : 2010

Charlotte Proudhon, Déborah Bourc'his (2010 Jun 1)

[Evolution of genomic imprinting in mammals: what a zoo!].

Médecine sciences : M/S : 497-503 : DOI : 10.1051/medsci/2010265497 En savoir plus
Résumé

Genomic imprinting imposes an obligate mode of biparental reproduction in mammals. This phenomenon results from the monoparental expression of a subset of genes. This specific gene regulation mechanism affects viviparous mammals, especially eutherians, but also marsupials to a lesser extent. Oviparous mammals, or monotremes, do not seem to demonstrate monoparental allele expression. This phylogenic confinement suggests that the evolution of the placenta imposed a selective pressure for the emergence of genomic imprinting. This physiological argument is now complemented by recent genomic evidence facilitated by the sequencing of the platypus genome, a rare modern day case of a monotreme. Analysis of the platypus genome in comparison to eutherian genomes shows a chronological and functional coincidence between the appearance of genomic imprinting and transposable element accumulation. The systematic comparative analyses of genomic sequences in different species is essential for the further understanding of genomic imprinting emergence and divergent evolution along mammalian speciation.

Replier
N Zamudio, D Bourc'his (2010 May 6)

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

Heredity : 92-104 : DOI : 10.1038/hdy.2010.53 En savoir plus
Résumé

Retrotransposable elements comprise around 50% of the mammalian genome. Their activity represents a constant threat to the host and has prompted the development of adaptive control mechanisms to protect genome architecture and function. To ensure their propagation, retrotransposons have to mobilize in cells destined for the next generation. Accordingly, these elements are particularly well suited to transcriptional networks associated with pluripotent and germinal states in mammals. The relaxation of epigenetic control that occurs in the early developing germline constitutes a dangerous window in which retrotransposons can escape from host restraint and massively expand. What could be observed as risky behavior may turn out to be an insidious strategy developed by germ cells to sense retrotransposons and hold them back in check. Herein, we review recent insights that have provided a detailed picture of the defense mechanisms that concur toward retrotransposon silencing in mammalian genomes, and in particular in the germline. In this lineage, retrotransposons are hit at multiple stages of their life cycle, through transcriptional repression, RNA degradation and translational control. An organized cross-talk between PIWI-interacting small RNAs (piRNAs) and various nuclear and cytoplasmic accessories provides this potent and multi-layered response to retrotransposon unleashing in early germ cells.

Replier

Année de publication : 2008

Alexei A Aravin, Ravi Sachidanandam, Deborah Bourc'his, Christopher Schaefer, Dubravka Pezic, Katalin Fejes Toth, Timothy Bestor, Gregory J Hannon (2008 Oct 17)

A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice.

Molecular cell : 785-99 : DOI : 10.1016/j.molcel.2008.09.003 En savoir plus
Résumé

piRNAs and Piwi proteins have been implicated in transposon control and are linked to transposon methylation in mammals. Here we examined the construction of the piRNA system in the restricted developmental window in which methylation patterns are set during mammalian embryogenesis. We find robust expression of two Piwi family proteins, MIWI2 and MILI. Their associated piRNA profiles reveal differences from Drosophila wherein large piRNA clusters act as master regulators of silencing. Instead, in mammals, dispersed transposon copies initiate the pathway, producing primary piRNAs, which predominantly join MILI in the cytoplasm. MIWI2, whose nuclear localization and association with piRNAs depend upon MILI, is enriched for secondary piRNAs antisense to the elements that it controls. The Piwi pathway lies upstream of known mediators of DNA methylation, since piRNAs are still produced in dnmt3L mutants, which fail to methylate transposons. This implicates piRNAs as specificity determinants of DNA methylation in germ cells.

Replier
Shantha K Mahadevaiah, Déborah Bourc'his, Dirk G de Rooij, Timothy H Bestor, James M A Turner, Paul S Burgoyne (2008 Jul 30)

Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation.

The Journal of cell biology : 263-76 : DOI : 10.1083/jcb.200710195 En savoir plus
Résumé

Chromosome synapsis during zygotene is a prerequisite for the timely homologous recombinational repair of meiotic DNA double-strand breaks (DSBs). Unrepaired DSBs are thought to trigger apoptosis during midpachytene of male meiosis if synapsis fails. An early pachytene response to asynapsis is meiotic silencing of unsynapsed chromatin (MSUC), which, in normal males, silences the X and Y chromosomes (meiotic sex chromosome inactivation [MSCI]). In this study, we show that MSUC occurs in Spo11-null mouse spermatocytes with extensive asynapsis but lacking meiotic DSBs. In contrast, three mutants (Dnmt3l, Msh5, and Dmc1) with high levels of asynapsis and numerous persistent unrepaired DSBs have a severely impaired MSUC response. We suggest that MSUC-related proteins, including the MSUC initiator BRCA1, are sequestered at unrepaired DSBs. All four mutants fail to silence the X and Y chromosomes (MSCI failure), which is sufficient to explain the midpachytene apoptosis. Apoptosis does not occur in mice with a single additional asynapsed chromosome with unrepaired meiotic DSBs and no disturbance of MSCI.

Replier
David Monk, Alexandre Wagschal, Philippe Arnaud, Pari-Sima Müller, Layla Parker-Katiraee, Déborah Bourc'his, Stephen W Scherer, Robert Feil, Philip Stanier, Gudrun E Moore (2008 May 16)

Comparative analysis of human chromosome 7q21 and mouse proximal chromosome 6 reveals a placental-specific imprinted gene, TFPI2/Tfpi2, which requires EHMT2 and EED for allelic-silencing.

Genome research : 1270-81 : DOI : 10.1101/gr.077115.108 En savoir plus
Résumé

Genomic imprinting is a developmentally important mechanism that involves both differential DNA methylation and allelic histone modifications. Through detailed comparative characterization, a large imprinted domain mapping to chromosome 7q21 in humans and proximal chromosome 6 in mice was redefined. This domain is organized around a maternally methylated CpG island comprising the promoters of the adjacent PEG10 and SGCE imprinted genes. Examination of Dnmt3l(-/+) conceptuses shows that imprinted expression for all genes of the cluster depends upon the germline methylation at this putative « imprinting control region » (ICR). Similarly as for other ICRs, we find its DNA-methylated allele to be associated with trimethylation of lysine 9 on histone H3 (H3K9me3) and trimethylation of lysine 20 on histone H4 (H4K20me3), whereas the transcriptionally active paternal allele is enriched in H3K4me2 and H3K9 acetylation. Our study reveals a novel placenta-specific transcript, TFPI2, which is expressed from the maternal allele in both humans and mice. Deficiency for the histone methyltransferase EHMT2 (also known as G9A) or for the Polycomb group protein EED, involved in repressive H3K9me2 and H3K27me3 respectively, leads to biallelic expression of Tfpi2 in the extra-embryonic lineages, whereas the other genes in the cluster maintain correct imprinting. Apart from the putative ICR, however, no other promoter regions within the domain exhibited allele-specific repressive histone modifications. This unexpected general lack of repressive histone modifications suggests that this domain may utilize a different silencing mechanism as compared to other imprinted domains.

Replier
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
Résumé

Replier
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.

Replier
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.

Replier
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.

Replier
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.

Replier

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.

Replier
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.

Replier
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.

Replier
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.

Replier
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.

Replier