Histone variants and chromatin homeostasis
Project leader: Erwan Delbarre
Histone H3 variants, including histone H3.3, contribute to the definition of chromatin domains. Histone chaperone complexes deposit H3.3 into specific genomic regions such as active genes and regulatory elements (HIRA), sites of DNA damage and of open chromatin (HIRA), and heterochromatin (DAXX/ATRX). Some pediatric gliomas called diffuse intrinsic pontine gliomas or DIPGs are linked to mutations in H3.3. The most prominent DIPG-linked H3.3 mutation is H3.3K27M, which results in global reduction of H3K27me3. Other H3.3 mutations include H3.3G34R, which affects other nearby H3 modifications.
- Mechanisms of deposition of H3.3 into chromatin
- Role of H3.3 on chromatin homeostasis
- Impact of H3.3 mutations on nuclear architecture in gliobastomas
- Multi-step targeting process of H3.3 to chromatin via PML bodies functioning as ‘triage centers’ for H3.3 prior to loading on chromatin (Delbarre et al 2013 Genome Res 23, 440-451)
- Chromatin-bound oncoprotein DEK as ‘gate-keeper’ of chromatin for H3.3 deposition (Ivanauskiene et al 2014 Genome Res 24, 1584-1594).
- PML protein regulates H3.3 deposition and is important for maintance of heterochromatic states (www.ncbi.nlm.nih.gov/pubmed/28341773 - Debarre et al 2017 Genome Res 27, 913-21)