Épigenèse et développement des mammifères

Publications de l’équipe

Année de publication : 2013

Edith Heard, Danesh Moazed (2013 Jun 11)

Cell nucleus.

Current opinion in cell biology : 279-80 : DOI : 10.1016/j.ceb.2013.05.002 En savoir plus
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Chong-Jian Chen, Edith Heard (2013 May 21)

Small RNAs derived from structural non-coding RNAs.

Methods (San Diego, Calif.) : 76-84 : DOI : 10.1016/j.ymeth.2013.05.001 En savoir plus
Résumé

It has been shown in small RNA sequencing-based studies that some small RNA fragments are specifically processed from known structural non-coding RNAs, either through Dicer-dependent or Dicer-independent pathways. Although these small RNAs are often less abundant compared to microRNAs in normal mammalian tissues, they are always present in all sequenced libraries. In this paper, we use the ncPRO-seq pipeline, to describe different profiles of these small RNA fragments, and to discuss their potential processing pathways and functions. To assess whether more small RNA fragments can be detected in small RNA sequencing datasets, we decided to focus on small nuclear RNAs, abbreviated as snRNAs, which are associated with Sm ribonucleoproteins to form functional RNA-protein complexes. Here, we describe a group of small RNA fragments derived from snRNAs, which are typically highly enriched in regions bound by Sm proteins. Based on this, we propose the existence of a potential novel small RNA family associated with Sm proteins.

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Edith Heard (2013 Apr 17)

The dynamics of epigenetic changes in a range of organisms.

Current topics in developmental biology : xiii-xv : DOI : 10.1016/B978-0-12-416027-9.10000-2 En savoir plus
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Edda G Schulz, Edith Heard (2013 Mar 8)

Role and control of X chromosome dosage in mammalian development.

Current opinion in genetics & development : 109-15 : DOI : 10.1016/j.gde.2013.01.008 En savoir plus
Résumé

Many species have evolved sex chromosomes with highly divergent gene content, such as the X and Y chromosomes in mammals. As most non sex-specific genes probably need to be expressed at similar levels in males and females, dosage compensation mechanisms are in place to equalize the gene dosage between the sexes, and possibly also between sex chromosomes and autosomes. In mammals, one out of two X chromosomes is inactivated early during development in a process called X-chromosome inactivation that has been investigated intensively in the 50 years since it was discovered. Less is known about the potential functional roles of X-linked gene dosage, for example in controlling development in a sex-specific manner. In this review, we discuss the evolution of dosage compensation and how it is controlled during embryogenesis of mammals. In addition we will summarize evidence on the potential role of X chromosome number during early development.

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Catherine Corbel, Patricia Diabangouaya, Anne-Valerie Gendrel, Jennifer C Chow, Edith Heard (2013 Jan 31)

Unusual chromatin status and organization of the inactive X chromosome in murine trophoblast giant cells.

Development (Cambridge, England) : 861-72 : DOI : 10.1242/dev.087429 En savoir plus
Résumé

Mammalian X-chromosome inactivation (XCI) enables dosage compensation between XX females and XY males. It is an essential process and its absence in XX individuals results in early lethality due primarily to extra-embryonic defects. This sensitivity to X-linked gene dosage in extra-embryonic tissues is difficult to reconcile with the reported tendency of escape from XCI in these tissues. The precise transcriptional status of the inactive X chromosome in different lineages has mainly been examined using transgenes or in in vitro differentiated stem cells and the degree to which endogenous X-linked genes are silenced in embryonic and extra-embryonic lineages during early postimplantation stages is unclear. Here we investigate the precise temporal and lineage-specific X-inactivation status of several genes in postimplantation mouse embryos. We find stable gene silencing in most lineages, with significant levels of escape from XCI mainly in one extra-embryonic cell type: trophoblast giant cells (TGCs). To investigate the basis of this epigenetic instability, we examined the chromatin structure and organization of the inactive X chromosome in TGCs obtained from ectoplacental cone explants. We find that the Xist RNA-coated X chromosome has a highly unusual chromatin content in TGCs, presenting both heterochromatic marks such as H3K27me3 and euchromatic marks such as histone H4 acetylation and H3K4 methylation. Strikingly, Xist RNA does not form an overt silent nuclear compartment or Cot1 hole in these cells. This unusual combination of silent and active features is likely to reflect, and might underlie, the partial activity of the X chromosome in TGCs.

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Année de publication : 2012

Tim Pollex, Edith Heard (2012 Nov 13)

Recent advances in X-chromosome inactivation research.

Current opinion in cell biology : 825-32 : DOI : 10.1016/j.ceb.2012.10.007 En savoir plus
Résumé

X-chromosome inactivation is the mechanism ensuring dosage compensation in mammals. It is regulated by the X-inactivation center (Xic), which harbors the main regulator of XCI, the long non-coding RNA Xist. In the past two years significant advances have been made in our understanding of how Xist is regulated by its neighbors in the Xic and in a developmental context. New technologies, such as chromosome conformation capture and live cell imaging, have helped us understand the topological organization of the Xic and the dynamics of this locus during differentiation. Here, we will describe some of the most recent findings made in X-inactivation research with a special focus on the regulation of Xist and the spatial organization of the Xic.

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Année de publication : 2011

Anne-Valerie Gendrel, Edith Heard (2011 Nov 10)

Fifty years of X-inactivation research.

Development (Cambridge, England) : 5049-55 : DOI : 10.1242/dev.068320 En savoir plus
Résumé

The third X-inactivation meeting ‘Fifty years of X-inactivation research’, which celebrated the fiftieth anniversary of Mary Lyon’s formulation of the X-inactivation hypothesis, was an EMBO workshop held in Oxford, UK, in July 2011. This conference brought together the usual suspects from the field, as well as younger researchers, to discuss recent advances in X-inactivation research. Here, we review the results presented at the meeting and highlight some of the exciting progress that has been made. We also discuss the future challenges for the field, which aim to further our understanding of the developmental regulation of X inactivation, the randomness (or skewing) of X inactivation, and the diverse strategies used by mammalian species to mediate X inactivation.

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Elphège P Nora, Bryan R Lajoie, Edda G Schulz, Luca Giorgetti, Ikuhiro Okamoto, Nicolas Servant, Tristan Piolot, Nynke L van Berkum, Johannes Meisig, John Sedat, Joost Gribnau, Emmanuel Barillot, Nils Blüthgen, Job Dekker, Edith Heard (2011 Oct 3)

Spatial partitioning of the regulatory landscape of the X-inactivation centre.

Nature : 381-5 : DOI : 10.1038/nature11049 En savoir plus
Résumé

In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.

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Edith Heard, James Turner (2011 Jul 7)

Function of the sex chromosomes in mammalian fertility.

Cold Spring Harbor perspectives in biology : a002675 : DOI : 10.1101/cshperspect.a002675 En savoir plus
Résumé

The sex chromosomes play a highly specialized role in germ cell development in mammals, being enriched in genes expressed in the testis and ovary. Sex chromosome abnormalities (e.g., Klinefelter [XXY] and Turner [XO] syndrome) constitute the largest class of chromosome abnormalities and the commonest genetic cause of infertility in humans. Understanding how sex-gene expression is regulated is therefore critical to our understanding of human reproduction. Here, we describe how the expression of sex-linked genes varies during germ cell development; in females, the inactive X chromosome is reactivated before meiosis, whereas in males the X and Y chromosomes are inactivated at this stage. We discuss the epigenetics of sex chromosome inactivation and how this process has influenced the gene content of the mammalian X and Y chromosomes. We also present working models for how perturbations in sex chromosome inactivation or reactivation result in subfertility in the major classes of sex chromosome abnormalities.

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Sandrine Augui, Elphège P Nora, Edith Heard (2011 May 19)

Regulation of X-chromosome inactivation by the X-inactivation centre.

Nature reviews. Genetics : 429-42 : DOI : 10.1038/nrg2987 En savoir plus
Résumé

X-chromosome inactivation (XCI) ensures dosage compensation in mammals and is a paradigm for allele-specific gene expression on a chromosome-wide scale. Important insights have been made into the developmental dynamics of this process. Recent studies have identified several cis- and trans-acting factors that regulate the initiation of XCI via the X-inactivation centre. Such studies have shed light on the relationship between XCI and pluripotency. They have also revealed the existence of dosage-dependent activators that trigger XCI when more than one X chromosome is present, as well as possible mechanisms underlying the monoallelic regulation of this process. The recent discovery of the plasticity of the inactive state during early development, or during cloning, and induced pluripotency have also contributed to the X chromosome becoming a gold standard in reprogramming studies.

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Martin Escamilla-Del-Arenal, Simao Teixeira da Rocha, Edith Heard (2011 May 1)

Evolutionary diversity and developmental regulation of X-chromosome inactivation.

Human genetics : 307-27 : DOI : 10.1007/s00439-011-1029-2 En savoir plus
Résumé

X-chromosome inactivation (XCI) results in the transcriptional silencing of one X-chromosome in females to attain gene dosage parity between XX female and XY male mammals. Mammals appear to have developed rather diverse strategies to initiate XCI in early development. In placental mammals XCI depends on the regulatory noncoding RNA X-inactive specific transcript (Xist), which is absent in marsupials and monotremes. Surprisingly, even placental mammals show differences in the initiation of XCI in terms of Xist regulation and the timing to acquire dosage compensation. Despite this, all placental mammals achieve chromosome-wide gene silencing at some point in development, and this is maintained by epigenetic marks such as chromatin modifications and DNA methylation. In this review, we will summarise recent findings concerning the events that occur downstream of Xist RNA coating of the inactive X-chromosome (Xi) to ensure its heterochromatinization and the maintenance of the inactive state in the mouse and highlight similarities and differences between mammals.

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Ikuhiro Okamoto, Catherine Patrat, Dominique Thépot, Nathalie Peynot, Patricia Fauque, Nathalie Daniel, Patricia Diabangouaya, Jean-Philippe Wolf, Jean-Paul Renard, Véronique Duranthon, Edith Heard (2011 Apr 8)

Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development.

Nature : 370-4 : DOI : 10.1038/nature09872 En savoir plus
Résumé

X-chromosome inactivation (XCI) in female mammals allows dosage compensation for X-linked gene products between the sexes. The developmental regulation of this process has been extensively investigated in mice, where the X chromosome of paternal origin (Xp) is silenced during early embryogenesis owing to imprinted expression of the regulatory RNA, Xist (X-inactive specific transcript). Paternal XCI is reversed in the inner cell mass of the blastocyst and random XCI subsequently occurs in epiblast cells. Here we show that other eutherian mammals have very different strategies for initiating XCI. In rabbits and humans, the Xist homologue is not subject to imprinting and XCI begins later than in mice. Furthermore, Xist is upregulated on both X chromosomes in a high proportion of rabbit and human embryo cells, even in the inner cell mass. In rabbits, this triggers XCI on both X chromosomes in some cells. In humans, chromosome-wide XCI has not initiated even by the blastocyst stage, despite the upregulation of XIST. The choice of which X chromosome will finally become inactive thus occurs downstream of Xist upregulation in both rabbits and humans, unlike in mice. Our study demonstrates the remarkable diversity in XCI regulation and highlights differences between mammals in their requirement for dosage compensation during early embryogenesis.

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Edda G Schulz, Elphège P Nora, Edith Heard (2011 Feb 8)

Rnf12–a jack of all trades in X inactivation?

PLoS genetics : e1002002 : DOI : 10.1371/journal.pgen.1002002 En savoir plus
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Année de publication : 2010

Elphège P Nora, Edith Heard (2010 Oct 19)

[Establishing transcriptional silencing of the X chromosome during early embryogenesis].

Biologie aujourd'hui : 199-204 : DOI : 10.1051/jbio/2010013 En savoir plus
Résumé

Early development of female mammals is accompanied by transcriptional inactivation of one of their two X chromosomes. This process, known as X-chromosome inactivation, relies on monoallelic activation of the Xist gene. Xist produces a non-coding RNA that can coat the chromosome from which it is transcribed in cis and trigger its silencing. How Xist expression is controlled and how it initiates transcriptional repression are central questions for our understanding of how this chromosome-wide monoallelic program is expressed. Several trans-acting factors have been identified as regulators of Xist expression. Interestingly, some Xist activators are encoded by the X chromosome itself, thereby efficiently promoting Xist expression in females (XX) but not in males (XY). Female cells also display transient physical pairing between their two X chromosomes at the level of their Xics (X inactivation centers) during the time window when X inactivation is initiated. It has been proposed that these pairing events may play a role in Xist activation and its monoallelic regulation. Xist RNA accumulates over the X chromosome from which it is expressed and rapidly triggers the exclusion of the transcription machinery. Genic sequences are initially located outside of this Xist RNA coated domain but as they become progressively silenced they are relocated into this silent nuclear compartment created by Xist. However genes are not all silenced with the same kinetics. Furthermore, some genes can escape X inactivation and remain located outside the Xist-coated compartment. Recent findings have revealed that young, active LINE-1 retrotransposons are expressed from the inactive X chromosome and may facilitate X inactivation, particularly in regions of the X that would otherwise be prone to escape.

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Jennifer C Chow, Edith Heard (2010 Oct 15)

Nuclear organization and dosage compensation.

Cold Spring Harbor perspectives in biology : a000604 : DOI : 10.1101/cshperspect.a000604 En savoir plus
Résumé

Dosage compensation is a strategy to deal with the imbalance of sex chromosomal gene products relative to autosomes and also between the sexes. The mechanisms that ensure dosage compensation for X-chromosome activity have been extensively studied in mammals, worms, and flies. Although each entails very different mechanisms to equalize the dose of X-linked genes between the sexes, they all involve the co-ordinate regulation of hundreds of genes specifically on the sex chromosomes and not the autosomes. In addition to chromatin modifications and changes in higher order chromatin structure, nuclear organization is emerging as an important component of these chromosome-wide processes and in the specific targeting of dosage compensation complexes to the sex chromosomes. Preferential localization within the nucleus and 3D organization are thought to contribute to the differential treatment of two identical homologs within the same nucleus, as well as to the chromosome-wide spread and stable maintenance of heterochromatin.

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