Mammalian Developmental Epigenetics

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Edith Heard Chef d'équipe Tel:

Epigenetics concerns changes in gene expression states that are stable over rounds of cell division, but do not involve changes in the underlying DNA sequence of the organism.

Figure 1 : X inactivation involves silencing of 1 of the 2 X chromosomes occurs during development (left) via the non-coding XIst RNA (right).
Figure 1 : X inactivation involves silencing of 1 of the 2 X chromosomes occurs during development (left) via the non-coding XIst RNA (right).

In female mammals, one of the two X chromosomes is transcriptionally silenced during early development to compensate for the double ‘dose’ of X-linked gene products in females (XX) when compared to males (XY). This process, known as X-chromosome inactivation (XCI), represents a paradigm for developmental epigenetics. A unique locus, the X-inactivation centre (Xic), initiates this process. The Xic produces a non-coding, regulatory RNA called Xist, which “coats” the X chromosome to be inactivated (Figure 1). We are interested in understanding the mechanisms by which X inactivation is initiated and maintained, via chromatin proteins, non-coding RNAs and DNA methylation. Understanding the epigenetics of X inactivation should provide important insights into diseases such as cancer, where deregulation of epigenetic states can play an important role.

 

Our group uses a combination of molecular genetics and cell biology approaches on embryos, embryonic stem cells and somatic cells. We are particularly interested in the roles that non-coding RNAs, chromatin changes and nuclear organisation might play in X inactivation and gene expression in general. To this end we use multi-dimensional fluorescence imaging techniques, in both fixed and living cells, as well as genomic approaches to define chromatin and transcriptional states. Our studies on embryos and differentiating ES cells have shown that X inactivation is a highly dynamic process during early embryogenesis. We have also shown that the presence of two active X chromosomes leads to a delay in differentiation kinetics until X inactivation is achieved.

 

Figure 2: Random monoallelic expression of several autosomal loci was revealed using allele-specific analyses in clonal neuronal progenitor cells and RNA FISH analyses in vivo in inbred mice (brain section of P6 stage shown with Sox2 biallelic expression and two monoallelic genes, Acyp2 and Cnrip1)
Figure 2: Random monoallelic expression of several autosomal loci was revealed using allele-specific analyses in clonal neuronal progenitor cells and RNA FISH analyses in vivo in inbred mice (brain section of P6 stage shown with Sox2 biallelic expression and two monoallelic genes, Acyp2 and Cnrip1)

X Inactivation is triggered thanks to the lncRNA Xist, which coats the chromosome and induces silencing. We recently showed that the region that produces Xist (the X-inactivation centre) is organised into two topologically associating domains of sequence interactions (TADs) and uncovered a new level of chromosome folding in the mouse genome (Nora et al, 2012). Physical modelling has enabled us to predict the key regions of a chromatin fibre that allow it to fold in 3D (Giorgetti et al, 2014). Recently we have also investigated the degree to which autosomal loci show monoallelic expression across the genome. We found about 2% of loci show random monoallelic expression (RME) and that this is clonally heritable, similarly to X-inactivation. However RME is highly tissue and stage-specific implying that it allows a certain degree of plasticity in cellular expression patterns. Importantly, some of the RME genes we identified have specific roles in development and have been linked to autosomal dominant disorders (Gendrel et al, 2014). Finally, in the context of our collaboration with the medical section of the Institut Curie, we are investigating the epigenetic and genetic integrity of the inactive X chromosome in human breast cancer. Given the increasing realization that epigenetic instability is implicated on carcinogenesis, we are using the inactive X chromosome as a model system to assess this in different types of breast tumor.

 

Key publications

Year of publication 2013

Luca Giorgetti, Rafael Galupa, Elphège P Nora, Tristan Piolot, France Lam, Job Dekker, Guido Tiana, Edith Heard (2013 Nov 15)

Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription.

Cell : 950-63 : DOI : 10.1016/j.cell.2014.03.025
Simão Teixeira da Rocha, Valentina Boeva, Martin Escamilla-Del-Arenal, Katia Ancelin, Camille Granier, Neuza Reis Matias, Serena Sanulli, Jen Chow, Edda Schulz, Christel Picard, Syuzo Kaneko, Kristian Helin, Danny Reinberg, A Francis Stewart, Anton Wutz, Raphaël Margueron, Edith Heard (2013 Nov 4)

Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome.

Molecular cell : 301-16 : DOI : 10.1016/j.molcel.2014.01.002
Anne-Valerie Gendrel, Mikael Attia, Chong-Jian Chen, Patricia Diabangouaya, Nicolas Servant, Emmanuel Barillot, Edith Heard (2013 Sep 6)

Developmental dynamics and disease potential of random monoallelic gene expression.

Developmental cell : 366-80 : DOI : 10.1016/j.devcel.2014.01.016
Edda G Schulz, Johannes Meisig, Tomonori Nakamura, Ikuhiro Okamoto, Anja Sieber, Christel Picard, Maud Borensztein, Mitinori Saitou, Nils Blüthgen, Edith Heard (2013 Jul 6)

The two active X chromosomes in female ESCs block exit from the pluripotent state by modulating the ESC signaling network.

Cell stem cell : 203-16 : DOI : 10.1016/j.stem.2013.11.022

Year of publication 2011

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
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
All publications