Description of the PhD thesis project
During ontogeny, chromatin modifiers
contribute to the orchestration of spatiotemporal gene expression programs that
underlie early development and organogenesis. The Polycomb repressive complex 2
(PRC2) is one of such central epigenetic remodelers. It is key for transmitting
correct chromatin information from parent to offspring during the formation of
the mouse germline. PRC2 methylates lysine 27 on histone H3 (H3K27me2/3), a
crucial step for the formation of closed chromatin structure refractory to transcription.
PRC2 cofactors modulates its enzymatic activity, influencing the H3K27me3
pattern. Among them, we recently characterized EZHIP as a negative regulator of
PRC2 in gametes. Although Ezhip KO animals are viable, mouse females display a
reduce fertility phenotype.
We are currently investigating phenotypic and
molecular changes upon maternal loss of EZHIP in oocyte, we have already
gathered important results concerning its role in maintenance of gene
imprinting in the progeny. Besides, preliminary evidences indicate that upon
loss of maternal and paternal EZHIP, the progeny displays a variety of subtle
phenotypes. Further investigation is needed to understand how PRC2-dependent
transcriptional changes affect early post-natal life and adulthood.
This project will aim at deciphering the role
of paternal EZHIP in the germline and upon its transmission at different stage
of mouse life, using low input CUT&RUN and RNAseq technologies to assess
chromatin and transcriptional changes.
International, interdisciplinary & intersectoral
aspects of the project
International: the student
will be mentored by Dr. Maria-Elena Torres-Padilla, Director of the Institute
of Epigenetics and Stem cells at HelmHoltz Zentrum, Munchen Germany.
Intersectoral: A one-day
immersion in a Start-up will be organized.
Interdisciplinary: the project
relies both on biology and informatics. The student will follow specific
training for bio-info.
Recent publications
- Richart L, Picod-Chedotel ML,
Wassef M, Macario M, Aflaki S, Salvador MA, Héry T, Dauphin A, Wicinski J,
Chevrier V, Pastor S, Guittard G, Le Cam S, Kamhawi H, Castellano R, Guasch G,
Charafe-Jauffret E, Heard E, Margueron#
R and Ginestier# C. XIST loss impairs mammary stem cell differentiation and
increases tumorigenicity through Mediator hyperactivation. Cell. 2022 Jun
9;185(12):2164-2183.e25. doi: 10.1016/j.cell.2022.04.034. Epub 2022 May 20.
PMID: 35597241
- Holoch D, Wassef M, Lövkvist C#,
Zielinski D, Aflaki S, Lombard D, Héry T, Loew D, Howard M & R Margueron#. A cis-acting mechanism
mediates transcriptional memory at Polycomb target genes in mammals. Nature
Genetics, 2021 Nov 15. doi: 10.1038/s41588-021-00964-2.
- Ragazzini R, Pérez-Palacios R,
Baymaz HI, Diop S, Ancelin K, Zielinski D, Michaud A, Givelet M, Borsos M,
Aflaki S, Legoix P, Jansen PWTC, Servant N, Torres-Padilla ME, Bourc’his D,
Fouchet P, Vermeulen M and Margueron# R.
EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells, Nat
Commun. 2019, Aug 26; 10(1): 3858.
- Wassef M, Luscan A, Aflaki S,
Zielinski D., Jansen P, Baymaz I, Battistella A, Kersouani C, Servant N,
Wallace MR, Romero P, Kosmider O, Just PA, Hivelin M, Jacques S,
Vincent-Salomon A, Vermeulen M, Vidaud M, Pasmant E & Margueron# R. EZH1/2 function mostly within canonical PRC2 and
exhibit proliferation-dependent redundancy that shapes mutational signatures in
cancer, PNAS, 2019 Mar 26; 116(13): 6075-6080. doi: 10.1073/pnas.1814634116.
Campagne A, Lee MK, Zielinski D, Michaud A, Le
Corre S, Dingli F, Chen H, Shahidian LZ, Vassilev I, Servant N, Loew D, Pasmant
E, Postel-Vinay S, Wassef M, Margueron#
R. BAP1 complex promotes transcription by opposing PRC1-mediated H2A
ubiquitylation. Nat Commun. 2019 Jan 21; 10(1): 348. doi:
10.1038/s41467-018-08255-x.