Download Epigenetics concerns changes in gene expression states that are

Mammalian Developmental Epigenetics
U934/UMR3215 – Genetics and Developmental Biology
Edith Heard
Chef d'équipe
[email protected]
Tel: +33 1 56 24 66 91
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.
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, noncoding 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.
Figure 1 : X inactivation involves silencing of 1 of
the 2 X chromosomes occurs during development
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
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1
Mammalian Developmental Epigenetics
U934/UMR3215 – Genetics and Developmental Biology
(left) via the non-coding XIst RNA (right).
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 Xinactivation. 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.
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 allelespecific 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)
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2
Mammalian Developmental Epigenetics
U934/UMR3215 – Genetics and Developmental Biology
Key publications
Year of publication 2017
Maud Borensztein, Laurène Syx, Katia Ancelin, Patricia Diabangouaya, Christel Picard, Tao Liu,
Jun-Bin Liang, Ivaylo Vassilev, Rafael Galupa, Nicolas Servant, Emmanuel Barillot, Azim Surani,
Chong-Jian Chen, Edith Heard (2017 Jan 31)
Xist-dependent imprinted X inactivation and the early developmental
consequences of its failure.
Nature structural & molecular biology : DOI : 10.1038/nsmb.3365
Year of publication 2016
Luca Giorgetti, Bryan R Lajoie, Ava C Carter, Mikael Attia, Ye Zhan, Jin Xu, Chong Jian Chen,
Noam Kaplan, Howard Y Chang, Edith Heard, Job Dekker (2016 Jul 21)
Structural organization of the inactive X chromosome in the mouse.
Nature : DOI : 10.1038/nature18589
Year of publication 2014
Luca Giorgetti, Rafael Galupa, Elphège P Nora, Tristan Piolot, France Lam, Job Dekker, Guido
Tiana, Edith Heard (2014 May 1)
Predictive polymer modeling reveals coupled fluctuations in chromosome
conformation and transcription.
Cell : 950-63 : DOI : 10.1016/j.cell.2014.03.025
Anne-Valerie Gendrel, Mikael Attia, Chong-Jian Chen, Patricia Diabangouaya, Nicolas Servant,
Emmanuel Barillot, Edith Heard (2014 Feb 24)
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 (2014 Feb 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,
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3
Mammalian Developmental Epigenetics
U934/UMR3215 – Genetics and Developmental Biology
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
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 4