ARNs non-codants, Différenciation et Développement

Chef d'equipe :
Claire ROUGEULLE



Research in the Rougeulle lab focuses on the emblematic process of X chromosome inactivation, with the aim to elucidate how such a chromosome-wide epigenetic silencing is achieved and regulated in various mammalian species. More generally, we are interested in the epigenetic control of gene expression in relation to cell identity and fate, the contribution of long noncoding RNA genes and transposable elements to these processes and the plasticity of epigenetic regulations in evolution.

We use a variety of mouse and primate pluripotent stem cells and their differentiated derivatives to recapitulate key developmental stages and cellular states. Our experimental strategy combines genome engineering (CRISPR) with single cell analyses, large scale transcriptomic and epigenomic investigations and 3D topological studies.

Mots Clés :   Epigenetics; X-chromosome inactivation; noncoding genome; human stem cells; pluripotency; cell reprogramming and differentiation; primate evolution

Nos projets de recherche:

Human X-inactivation in a dish

Evolution of X-inactivation across primates

Plasticity of the noncoding genome

X chromosome inactivation is critical for women development and linked to sex-specific susceptibilities to various diseases. To understand how XCI contributes to male-female differences, we model, in vitro, key steps of X-inactivation using, as an entry point, Human Embryonic Stem cells (hESC). hESC are reprogrammed to discover how XCI is initially established during the first days of embryonic development with a particular focus on the role of structural noncoding RNAs such as XIST and XACT. hESC are differentiated into specific cell types to assess the plasticity of XCI in distinct somatic tissues, including the hematopoietic compartment and organized tissue through the use of organoids.
Remarkable differences exist in the way X chromosome inactivation is set up between human and mouse in connection with drastically different network of regulatory lncRNA genes which our group contributed to decipher. We are now exploring phenotypic and mechanistic variability in X-inactivation across primates using non-human primate pluripotent stem cells to probe the degree of genetic and epigenetic innovation across a limited timescale, and the contribution of the noncoding genome to such evolution.
The noncoding genome participates to the establishment of gene expression programs, and, as such, to cell identity and fate. It encompasses a vast repertoire of lncRNA genes (LRGs) – a fraction of which derives from endogenous retroviruses – whose function may be conveyed by distinct modules, such as the RNA itself, the genomic locus, the act of transcription, or any downstream smaller RNA by-products. X-inactivation is a striking example of a process controlled by LRGs acting at multiple levels and through diverse mechanisms. Our aim is to explore LRG’s versatility to understand whether a given LRG could play multiple functions in various developmental and cellular contexts, and how the underlying mechanisms may vary accordingly.

Financements :