Décisions épigénétiques et reproduction chez les mammifères

Publications

Année de publication : 2021

Deborah Bourc'his (2021 Jul 30)

Metastable epialleles are stable in their instability.

Nature genetics : 1121-1123 : DOI : 10.1038/s41588-021-00907-x En savoir plus
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Jihene Klibi, Claudine Joseph, Marc Delord, Aurelie Teissandier, Bruno Lucas, Christine Chomienne, Antoine Toubert, Deborah Bourc'his, Fabien Guidez, Kamel Benlagha (2021 Jul 20)

PLZF Acetylation Levels Regulate NKT Cell Differentiation.

Journal of immunology (Baltimore, Md. : 1950) : 809-823 : DOI : 10.4049/jimmunol.2001444 En savoir plus
Résumé

The transcription factor promyelocytic leukemia zinc finger (PLZF) is encoded by the BTB domain-containing 16 () gene. Its repressor function regulates specific transcriptional programs. During the development of invariant NKT cells, PLZF is expressed and directs their effector program, but the detailed mechanisms underlying PLZF regulation of multistage NKT cell developmental program are not well understood. This study investigated the role of acetylation-induced PLZF activation on NKT cell development by analyzing mice expressing a mutant form of PLZF mimicking constitutive acetylation (PLZF) mice. NKT populations in PLZF mice were reduced in proportion and numbers of cells, and the cells present were blocked at the transition from developmental stage 1 to stage 2. NKT cell subset differentiation was also altered, with T-bet NKT1 and RORγt NKT17 subsets dramatically reduced and the emergence of a T-betRORγt NKT cell subset with features of cells in early developmental stages rather than mature NKT2 cells. Preliminary analysis of DNA methylation patterns suggested that activated PLZF acts on the DNA methylation signature to regulate NKT cells’ entry into the early stages of development while repressing maturation. In wild-type NKT cells, deacetylation of PLZF is possible, allowing subsequent NKT cell differentiation. Interestingly, development of other innate lymphoid and myeloid cells that are dependent on PLZF for their generation is not altered in PLZF mice, highlighting lineage-specific regulation. Overall, we propose that specific epigenetic control of PLZF through acetylation levels is required to regulate normal NKT cell differentiation.

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Tomasz Chelmicki, Emeline Roger, Aurélie Teissandier, Mathilde Dura, Lorraine Bonneville, Sofia Rucli, François Dossin, Camille Fouassier, Sonia Lameiras, Deborah Bourc'his (2021 Jan 14)

mA RNA methylation regulates the fate of endogenous retroviruses.

Nature : 312-316 : DOI : 10.1038/s41586-020-03135-1 En savoir plus
Résumé

Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that affect genome regulation and cell physiology throughout their RNA-centred life cycle. Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases. Here, using an unbiased genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify mA RNA methylation as a way to restrict ERVs. Methylation of ERV mRNAs is catalysed by the complex of methyltransferase-like METTL3-METTL14 proteins, and we found that depletion of METTL3-METTL14, along with their accessory subunits WTAP and ZC3H13, led to increased mRNA abundance of intracisternal A-particles (IAPs) and related ERVK elements specifically, by targeting their 5′ untranslated region. Using controlled auxin-dependent degradation of the METTL3-METTL14 enzymatic complex, we showed that IAP mRNA and protein abundance is dynamically and inversely correlated with mA catalysis. By monitoring chromatin states and mRNA stability upon METTL3-METTL14 double depletion, we found that mA methylation mainly acts by reducing the half-life of IAP mRNA, and this occurs by the recruitment of the YTHDF family of mA reader proteins. Together, our results indicate that RNA methylation provides a protective effect in maintaining cellular integrity by clearing reactive ERV-derived RNA species, which may be especially important when transcriptional silencing is less stringent.

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Giorgia Barucci, Deborah Bourc'his (2021 Jan 12)

Meiosis, a New Playground for Retrotransposon Evolution.

Developmental cell : 1-2 : DOI : S1534-5807(20)31018-2 En savoir plus
Résumé

Retrotransposons provide both threats and evolutionary opportunities for their hosts. In this issue of Developmental Cell, Laureau et al. describe a fascinating host-retrotransposon relationship that may lead to retrotransposon domestication: Ty3/Gypsy exploit meiosis networks to sustain their transcription, while the host deploys RNA-binding proteins to prevent their translation.

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Année de publication : 2020

J Barberet, C Binquet, M Guilleman, A Doukani, C Choux, C Bruno, A Bourredjem, C Chapusot, D Bourc'his, Y Duffourd, P Fauque (2020 Dec 15)

Do assisted reproductive technologies and in vitro embryo culture influence the epigenetic control of imprinted genes and transposable elements in children?

Human reproduction (Oxford, England) : 479-492 : DOI : 10.1093/humrep/deaa310 En savoir plus
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Do assisted reproductive technologies (ART) and in vitro embryo culture influence the epigenetic control of imprinted genes (IGs) and transposable elements (TEs) in children?

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Raquel Pérez-Palacios, Patricia Fauque, Aurélie Teissandier, Déborah Bourc'his (2020 Sep 18)

Deciphering the Early Mouse Embryo Transcriptome by Low-Input RNA-Seq.

Methods in molecular biology (Clifton, N.J.) : 189-205 : DOI : 10.1007/978-1-0716-0958-3_13 En savoir plus
Résumé

Early preimplantation embryos are precious and scarce samples that contain limited numbers of cells, which can be problematic for quantitative gene expression analyses. Nonetheless, low-input genome-wide techniques coupled with cDNA amplification steps have become a gold standard for RNA profiling of as minimal as a single blastomere. Here, we describe a single-cell/single-embryo RNA sequencing (RNA-seq) method, from embryo collection to sample validation steps prior to DNA library preparation and sequencing. Key quality controls and external Spike-In normalization approaches are also detailed.

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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 26)

EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells.

Nature communications : 10 : 1-18 : 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
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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
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