Décisions épigénétiques et reproduction chez les mammifères

Publications

Année de publication : 2020

Antoine Molaro, Harmit S Malik, Deborah Bourc'his (2020 Feb 21)

Dynamic evolution of de novo DNA methyltransferases in rodent and primate genomes.

Molecular biology and evolution : DOI : msaa044 En savoir plus
Résumé

Transcriptional silencing of retrotransposons via DNA methylation is paramount for mammalian fertility and reproductive fitness. During germ cell development, most mammalian species utilize the de novo DNA methyltransferases DNMT3A and DNMT3B to establish DNA methylation patterns. However, many rodent species deploy a third enzyme, DNMT3C, to selectively methylate the promoters of young retrotransposon insertions in their germline. The evolutionary forces that shaped DNMT3C’s unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred around 60Mya in the last common ancestor of muroid rodents. Importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds has undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has instead evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result of an ongoing evolutionary arms race with young retrotransposon lineages in muroid genomes. Interestingly, although primates lack DNMT3C, we find that the N-terminus of DNMT3A has also evolved under diversifying selection. Thus, the N-termini of two independent de novo methylation enzymes have evolved under diversifying selection in rodents and primates. We hypothesize that repression of young retrotransposons might be driving the recurrent innovation of a functional domain in the N-termini on germline DNMT3s in mammals.

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Aurélie Teissandier, Nicolas Servant, Emmanuel Barillot, Deborah Bourc'his (2020 Jan 1)

Tools and best practices for retrotransposon analysis using high-throughput sequencing data.

Mobile DNA : 52 : DOI : 10.1186/s13100-019-0192-1 En savoir plus
Résumé

Sequencing technologies give access to a precise picture of the molecular mechanisms acting upon genome regulation. One of the biggest technical challenges with sequencing data is to map millions of reads to a reference genome. This problem is exacerbated when dealing with repetitive sequences such as transposable elements that occupy half of the mammalian genome mass. Sequenced reads coming from these regions introduce ambiguities in the mapping step. Therefore, applying dedicated parameters and algorithms has to be taken into consideration when transposable elements regulation is investigated with sequencing datasets.

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Année de publication : 2019

Courtney W Hanna, Raquel Pérez-Palacios, Lenka Gahurova, Michael Schubert, Felix Krueger, Laura Biggins, Simon Andrews, Maria Colomé-Tatché, Deborah Bourc'his, Wendy Dean, Gavin Kelsey (2019 Oct 31)

Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues.

Genome biology : 225 : DOI : 10.1186/s13059-019-1833-x En savoir plus
Résumé

Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on the parent of origin and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages, and uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored.

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Roberta Ragazzini, Raquel Pérez-Palacios, Irem H Baymaz, Seynabou Diop, Katia Ancelin, Dina Zielinski, Audrey Michaud, Maëlle Givelet, Mate Borsos, Setareh Aflaki, Patricia Legoix, Pascal W T C Jansen, Nicolas Servant, Maria-Elena Torres-Padilla, Deborah Bourc'his, Pierre Fouchet, Michiel Vermeulen, Raphaël Margueron (2019 Aug 28)

EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells.

Nature communications : 3858 : DOI : 10.1038/s41467-019-11800-x En savoir plus
Résumé

The Polycomb group of proteins is required for the proper orchestration of gene expression due to its role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip in mice leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This does not affect the initial number of follicles but is associated with a reduction of follicles in aging. Our results suggest that mature oocytes Ezhip-/- might not be fully functional and indicate that fertility is strongly impaired in Ezhip-/- females. Altogether, our study uncovers EZHIP as a regulator of chromatin landscape in gametes.

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Maxim V C Greenberg, Deborah Bourc'his (2019 Aug 11)

The diverse roles of DNA methylation in mammalian development and disease.

Nature reviews. Molecular cell biology : 590-607 : DOI : 10.1038/s41580-019-0159-6 En savoir plus
Résumé

DNA methylation is of paramount importance for mammalian embryonic development. DNA methylation has numerous functions: it is implicated in the repression of transposons and genes, but is also associated with actively transcribed gene bodies and, in some cases, with gene activation per se. In recent years, sensitive technologies have been developed that allow the interrogation of DNA methylation patterns from a small number of cells. The use of these technologies has greatly improved our knowledge of DNA methylation dynamics and heterogeneity in embryos and in specific tissues. Combined with genetic analyses, it is increasingly apparent that regulation of DNA methylation erasure and (re-)establishment varies considerably between different developmental stages. In this Review, we discuss the mechanisms and functions of DNA methylation and demethylation in both mice and humans at CpG-rich promoters, gene bodies and transposable elements. We highlight the dynamic erasure and re-establishment of DNA methylation in embryonic, germline and somatic cell development. Finally, we provide insights into DNA methylation gained from studying genetic diseases.

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Maxim Greenberg, Aurélie Teissandier, Marius Walter, Daan Noordermeer, Deborah Bourc'his (2019 Apr 17)

Dynamic enhancer partitioning instructs activation of a growth-related gene during exit from naïve pluripotency.

eLife : DOI : 10.7554/eLife.44057 En savoir plus
Résumé

During early mammalian development, the chromatin landscape undergoes profound transitions. The gene-involved in growth control-provides a valuable model to study this window: upon exit from naïve pluripotency and prior to tissue differentiation, it undergoes a switch from a distal to a proximal promoter usage, accompanied by a switch from polycomb to DNA methylation occupancy. Using a mouse embryonic stem cell (ESC) system to mimic this period, we show here that four enhancers contribute to the promoter switch, concomitantly with dynamic changes in chromatin architecture. In ESCs, the locus is partitioned to facilitate enhancer contacts with the distal promoter. Relieving the partition enhances proximal promoter activity, as observed during differentiation or with genetic mutants. Importantly, we show that 3D regulation occurs upstream of the polycomb and DNA methylation pathways. Our study reveals the importance of multi-layered regulatory frameworks to ensure proper spatio-temporal activation of developmentally important genes.

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Virginie Carmignac, Julie Barberet, Julian Iranzo, Ronan Quéré, Magali Guilleman, Déborah Bourc'his, Patricia Fauque (2019 Mar 14)

Effects of assisted reproductive technologies on transposon regulation in the mouse pre-implanted embryo.

Human reproduction (Oxford, England) : 612-622 : DOI : 10.1093/humrep/dez020 En savoir plus
Résumé

Do assisted reproductive technologies (ARTs) impact on the expression of transposable elements (TEs) in preimplantation embryos?

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Année de publication : 2018

Anne C Ferguson-Smith, Deborah Bourc'his (2018 Oct 23)

The discovery and importance of genomic imprinting.

eLife : DOI : 10.7554/eLife.42368 En savoir plus
Résumé

The discovery of genomic imprinting by Davor Solter, Azim Surani and co-workers in the mid-1980s has provided a foundation for the study of epigenetic inheritance and the epigenetic control of gene activity and repression, especially during development. It also has shed light on a range of diseases, including both rare genetic disorders and common diseases. This article is being published to celebrate Solter and Surani receiving a 2018 Canada Gairdner International Award « for the discovery of mammalian genomic imprinting that causes parent-of-origin specific gene expression and its consequences for development and disease ».

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Raquel Pérez-Palacios, Deborah Bourc'his (2018 Jun 20)

A single-cell chromatin map of human embryos.

Nature cell biology : 742-744 : DOI : 10.1038/s41556-018-0134-z En savoir plus
Résumé

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Année de publication : 2017

C Choux, C Binquet, V Carmignac, C Bruno, C Chapusot, J Barberet, M Lamotte, P Sagot, D Bourc'his, P Fauque (2017 Dec 14)

The epigenetic control of transposable elements and imprinted genes in newborns is affected by the mode of conception: ART versus spontaneous conception without underlying infertility.

Human reproduction (Oxford, England) : 331-340 : DOI : 10.1093/humrep/dex366 En savoir plus
Résumé

Do assisted reproductive technologies alter DNA methylation and/or transcription of transposable elements and imprinted genes in cord blood and placenta?

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Aurélie Teissandier, Déborah Bourc'his (2017 Apr 27)

Gene body DNA methylation conspires with H3K36me3 to preclude aberrant transcription.

The EMBO journal : 1471-1473 : DOI : 10.15252/embj.201796812 En savoir plus
Résumé

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Yara Tarabay, Mayada Achour, Marius Teletin, Tao Ye, Aurélie Teissandier, Manuel Mark, Déborah Bourc'his, Stéphane Viville (2017 Mar 4)

Tex19 paralogs are new members of the piRNA pathway controlling retrotransposon suppression.

Journal of cell science : DOI : jcs.188763 En savoir plus
Résumé

Tex19 genes are mammalian specific and duplicated in Tex19.1 and Tex19.2 in some species, such as the mouse and rat. It has been demonstrated that mutant Tex19.1 males display a variable degree of infertility whereas they all upregulate MMERVK10C transposons in their germ line. In order to study the function of both paralogs in the mouse, we generated and studied double knockout (Tex19DKO) mutant mice. Adult Tex19DKO males exhibited a fully penetrant phenotype, similar to the most severe phenotype observed in single Tex19.1KO mice, with small testes and impaired spermatogenesis, defects in meiotic chromosome synapsis, persistence of DNA double-strand breaks during meiosis, lack of post-meiotic germ cells and upregulation of MMERVK10C expression. The phenotypic similarities with Piwi KO mice prompted us to check and then demonstrate, by immunoprecipitation and GST pulldown followed by mass spectrometry analyses, that TEX19 paralogs interact with PIWI proteins and their VPTEL domain directly binds piRNAs in adult testes. We therefore identified two new members of the postnatal piRNA pathway.

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Maxim V C Greenberg, Juliane Glaser, Máté Borsos, Fatima El Marjou, Marius Walter, Aurélie Teissandier, Déborah Bourc'his (2017 Jan 2)

Transient transcription in the early embryo sets an epigenetic state that programs postnatal growth.

Nature genetics : 110-118 : DOI : 10.1038/ng.3718 En savoir plus
Résumé

The potential for early embryonic events to program epigenetic states that influence adult physiology remains an important question in health and development. Using the imprinted Zdbf2 locus as a paradigm for the early programming of phenotypes, we demonstrate here that chromatin changes that occur in the pluripotent embryo can be dispensable for embryogenesis but instead signal essential regulatory information in the adult. The Liz (long isoform of Zdbf2) transcript is transiently expressed in early embryos and embryonic stem cells (ESCs). This transcription locally promotes de novo DNA methylation upstream of the Zdbf2 promoter, which antagonizes Polycomb-mediated repression of Zdbf2. Strikingly, mouse embryos deficient for Liz develop normally but fail to activate Zdbf2 in the postnatal brain and show indelible growth reduction, implying a crucial role for a Liz-dependent epigenetic switch. This work provides evidence that transcription during an early embryonic timeframe can program a stable epigenetic state with later physiological consequences.

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Année de publication : 2016

Joan Barau, Aurélie Teissandier, Natasha Zamudio, Stéphanie Roy, Valérie Nalesso, Yann Hérault, Florian Guillou, Déborah Bourc'his (2016 Nov 19)

The DNA methyltransferase DNMT3C protects male germ cells from transposon activity.

Science (New York, N.Y.) : 909-912 En savoir plus
Résumé

DNA methylation is prevalent in mammalian genomes and plays a central role in the epigenetic control of development. The mammalian DNA methylation machinery is thought to be composed of three DNA methyltransferase enzymes (DNMT1, DNMT3A, and DNMT3B) and one cofactor (DNMT3L). Here, we describe the discovery of Dnmt3C, a de novo DNA methyltransferase gene that evolved via a duplication of Dnmt3B in rodent genomes and was previously annotated as a pseudogene. We show that DNMT3C is the enzyme responsible for methylating the promoters of evolutionarily young retrotransposons in the male germ line and that this specialized activity is required for mouse fertility. DNMT3C reveals the plasticity of the mammalian DNA methylation system and expands the scope of the mechanisms involved in the epigenetic control of retrotransposons.

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Marius Walter, Aurélie Teissandier, Raquel Pérez-Palacios, Déborah Bourc'his (2016 Jan 27)

An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells.

eLife : DOI : 10.7554/eLife.11418 En savoir plus
Résumé

DNA methylation is extensively remodeled during mammalian gametogenesis and embryogenesis. Most transposons become hypomethylated, raising the question of their regulation in the absence of DNA methylation. To reproduce a rapid and extensive demethylation, we subjected mouse ES cells to chemically defined hypomethylating culture conditions. Surprisingly, we observed two phases of transposon regulation. After an initial burst of de-repression, various transposon families were efficiently re-silenced. This was accompanied by a reconfiguration of the repressive chromatin landscape: while H3K9me3 was stable, H3K9me2 globally disappeared and H3K27me3 accumulated at transposons. Interestingly, we observed that H3K9me3 and H3K27me3 occupy different transposon families or different territories within the same family, defining three functional categories of adaptive chromatin responses to DNA methylation loss. Our work highlights that H3K9me3 and, most importantly, polycomb-mediated H3K27me3 chromatin pathways can secure the control of a large spectrum of transposons in periods of intense DNA methylation change, ensuring longstanding genome stability.

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