"Histone variant H3.3 and cellular programs during development and cancer (2022-01-ALMOUZNI_SIMEONOV)" project details

× Help section

To download a PDF version of the PhD thesis project, please click on the PDF document in orange.

General information

Application closed

2022-01-ALMOUZNI_SIMEONOV

Development and cancer; Histone variants and marks; Animal models, Single cell, Omics.

Histone variant H3.3 and cellular programs during development and cancer

Director(s) and team

Geneviève Almouzni & Iva Simeonova

Chromatin Dynamics

Abstract

To shape the genome in 3 dimensions in the nucleus, DNA is organized into chromatin, of which the basic unit, the nucleosome core particle, comprises about 146 bp of DNA wrapped around histones. Importantly, histones exist as distinct variants with various post-translational modifications (PTM). In each cell type, their distinct genome distribution defines an epigenomic landscape. Strikingly, alterations in histone H3 variants have been reported in brain tumors in children and later in other types of cancers, and the interest in understanding their contribution to genome function is continuously increasing.   Our team is exploring the role of histone variants in genome organization and maintenance and their link to transcriptional regulation and lineage fate choices. We recently found that a unique amino acid (S31) in the histone variant H3.3 was absolutely essential to complete gastrulation in Xenopus embryos. Phosphorylation of this evolutionary conserved residue specific to the H3.3 variant also proved critical in transcriptional control during ES cell differentiation and macrophages activation. Thus, the use of specific histone variants for proper chromatin organization has emerged as essential for cell fate choices.   The PhD student will investigate histone H3.3 importance in cell fate changes, in the context of normal development and in pediatric glioblastoma. S/he will build on cellular and animal models established in the laboratory to follow cell fate by using cutting-edge transcriptomic approaches, combined with in silico analysis of public datasets. We hypothesize that unique H3.3S31 phosphorylation could promote transcription at key developmental loci and engage in/maintain specific cell fates. The regulation of H3.3 transcription by tissue-specific factors, and the H3.3S31 unique PTM cross-talk with neighboring residues could contribute to cell plasticity during normal physiology and would be high-jacked by tumor programs in cancers harboring H3.3 mutations.

Requirements to apply for the PhD thesis project

Applicants should have a strong desire to explore cell biological phenomena in an in vivo context, and should show solid capacity for independent and creative thinking. Background in molecular and cell biology, developmental biology, mouse genetics, and/or stem cell biology is strongly recommended. Background in immunology is a plus but not compulsory. The project highly relies on transcriptomic approaches. The applicant should have either experience in bioinformatics or a strong motivation to learn.