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Team Publications
Mammalian Developmental Epigenetics
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
Summary
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 Xinactivation 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.
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
Summary
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
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1
Team Publications
Mammalian Developmental Epigenetics
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.
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
Summary
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 Xinactivation 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.
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
Summary
X-chromosome inactivation (XCI) results in the transcriptional silencing of one Xchromosome 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 Xinactive 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.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2
Team Publications
Mammalian Developmental Epigenetics
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3