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.