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Reprogrammation épigénétique et Développement

Maud Borensztein

Projets de recherche

Lab opening: December 2020

 

Our group investigates X-chromosome reactivation during the specification of the germline. This female-specific reprogramming pathway is a paradigm of epigenetic resetting and fine gene-regulation control. A better understanding of the mechanisms involved in gene expression regulation and epigenetic memory is crucial, especially in the very unique context of the germ line formation.

Epigenetic memory plays a determinant role in locking cell fates through inheritance of chromatin modifications such as DNA methylation and histone marks. This is paramount for the stability of gene expression programs, cell identity and functions. In mammals, the most drastic transition in cell fate coincides with the emergence of the germline in the embryo. It involves a profound epigenetic remodelling of the cells. Occurring in both sexes, germline reprogramming is essential for the specialization of reproductive cells, and therefore, for the perpetuation of the species. However, in females specifically, reactivation of the entire inactive X chromosome, an epigenetic hallmark of female somatic cells, accompanies the acquisition of germline identity. Incidentally, this leads to a biallelic expression of X-linked gene in the germline precursors of XX females compared to XY males, at the onset of gonadal sex determination. The biological impact and significance of this sex-specific epigenetic characteristics is unknown. However, the presence of a non-reactivated X chromosome could be detrimental to homologous chromosome pairing and segregation in meiosis, and could lead to maternally inherited sex-chromosome aneuploidies such as XO and XXY syndromes in humans.

 

 

 

 

 

 

 

 

 

 

 

 

In the group, we aim to investigate the specificity and principles of female germline epigenetic reprogramming by :

1) Mapping the reshuffling of the epigenetic landscape on the active and inactive X chromosomes and in a sex-specific manner.

Techniques: mouse, cytometry, low-input CUT&RUN, ChIPseq, WGBS

2) Identifying the molecular mechanisms involved in X-chromosome reactivation in a culture-based system of germ cells.

Techniques: cell culture, mPGCLC, cytometry, RNAseq, CRISPR screen

3) Investigating the reciprocal influence between X-chromosome activity and global genome transcription.

Techniques: cell culture, mPGCLC, cell nornalized RNAseq, RNA-FISH

Ultimately, this work will have broader implications for sex-chromosome related infertility and aneuploidy syndromes, stem cell and reproductive medicine, as well as epigenetic inheritance and cancer.

 

Selection of publications :

Borensztein M*, Okamoto I*, Syx L, Guilbaud G, Picard C, Ancelin K, Galupa R, Diabangouaya P, Servant N, Barillot E, Surani A, Saitou M, Chen CJ, Anastassiadis K, Heard E. Contribution of epigenetic landscapes and transcription factors to X-chromosome reactivation in the inner cell mass. Nature Communications, 2017, 8 (1):1297; doi: 10.1038/s41467-017-01415-5.

Borensztein M, Syx L, Ancelin K, Diabangouya P, Picard C, Liu T, Liang JB, Vassilev Y, Galupa R, Servant N, Barillot E, Surani MA, Chen CJ, Heard E. Xist-dependent imprinted X inactivation and the early developmental consequences of its failure. Nature Structural and Molecular Biology, 2017, 24: 226-233; doi: 10.1038/nsmb.3365.

Zylicz JJ*, Borensztein M*, Wong FC, Huang Y, Lee C, Dietmann S, Surani MA. G9a regulates temporal preimplantation developmental program and lineage segregation in blastocysts. eLIFE, 2018, pii: e33361 ; doi: 10.7554/eLife.33361.

Borensztein M. Investigating the inner cell mass of the mouse blastocyst by combined immunofluorescence staining and RNA fluorescent in situ hybridization. Methods in Molecular Biology, 2020, doi:10.1007/978-1-0716-0958-3_11.

Borensztein M, Syx L, Servant N, Heard E. Transcriptome profiling of single mouse oocytes. Methods in Molecular Biology, 2018, 1818:51-65; doi: 10.1007/978-1-4939-8603-3_7.

 

List of all the publications :

Investigating the inner cell mass of the mouse blastocyst by combined immunofluorescence staining and RNA fluorescent in situ hybridization.
Borensztein M
Methods in Molecular Biology
doi:10.1007/978-1-0716-0958-3_11. In press (no PMID yet)

Understanding chromosome structure during early mouse development by single-cell Hi-C analysis.
Ranisavljevic N, Borensztein M, Ancelin K.
Methods in Molecular Biology,
doi: 10.1007/978-1-0716-0958-3_19. In press (no PMID yet)

Parental-to-embryo transition in chromosome organisation during early embryogenesis
Collombet S*, Ranisavljevic N*, Nagano T*, Varnai C, Shisode T, Leung W, Piolot T, Galupa R, Borensztein M, Servant N, Fraser P, Ancelin K, Heard E.
Nature
PMID: 32238933

Transcriptome profiling of single mouse oocytes.
Borensztein M, Syx L, Servant N, Heard E.
Methods in Molecular Biology
PMID: 29961255

G9a regulates temporal preimplantation developmental program and lineage segregation in blastocysts
Zylicz JJ*, Borensztein M*, Wong FC, Huang Y, Lee C, Dietmann S, Surani MA.
eLIFE
PMID: 29745895

Contribution of epigenetic landscapes and transcription factors to X-chromosome reactivation in the inner cell mass
Borensztein M*, Okamoto I*, Syx L, Guilbaud G, Picard C, Ancelin K, Galupa R, Diabangouaya P, Servant N, Barillot E, Surani A, Saitou M, Chen CJ, Anastassiadis K, Heard E.
Nature Communications
PMID: 29101321

Xist-dependent imprinted X inactivation and the early developmental consequences of its failure
Borensztein M, Syx L, Ancelin K, Diabangouya P, Picard C, Liu T, Liang JB, Vassilev Y, Galupa R, Servant N, Barillot E, Surani MA, Chen CJ, Heard E.
Nature Structural and Molecular Biology
PMID: 28134930

Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation
Ancelin K, Syx L, Borensztein M, Ranisavljevic N, Vassilev I, Briseño-Roa L, Liu T, Metzger E, Servant N, Barillot E, Chen CJ, Schüle R, Heard E.
eLIFE
PMID: 26836306

The two active X chromosomes in female ESCs block exit from the pluripotent state by modulating the ESC signalling network.
Schulz EG, Meisig J, Nakamura T, Okamoto I, Sieber A, Picard C, Borensztein M, Saitou M, Blüthgen N, Heard E.
Cell Stem Cell
PMID: 24506884

 

Membres

Team leader

Maud BORENSZTEIN

+33 (0)4 34 35 9605

Autres informations

Toutes les équipe de recherche

Mots-clés
Model organism studied
Mouse, embryonic stem cells, primordial germ cell like-cells
Biological process
Epigenetic reprogramming, X-chromosome reactivation, control of gene expression
Biological techniques
Single cell RNAseq, low-input epigenomics, bioinformatics, stem cell engineering