Histone H3.3 and chromatin homeostasis

Histone H3.3 and chromatin homeostasis

Erwan Delbarre, Kristin Vekterud

Histone H3 variants such as H3.3 contribute to the definition of chromatin domains. Dedicated histone H3.3 chaperones deposit H3.3 into specific genomic regions such as active genes and regulatory elements, sites of DNA damage and heterochromatin. A form of pediatric gliomas called diffuse intrinsic pontine glioma (DIPG) is caused by mutations in H3.3, among which H3.3K27M is the most prominent. H3.3K27M leads to a global reduction of H3K27me3, but other effects on nuclear organization are not known.

Ongoing research:

  • Mechanisms of H3.3 deposition into chromatin
  • Role of H3.3 on  maintenance of heterochromatin homeostasis
  • Impact of DIPG-causing H3.3 mutations on nuclear architecture

Recent findings:

  • Identfication of PML-associated domains (PADs); PML regulates H3.3 deposition and is important for maintance of heterochromatin PADs (Debarre et al 2017 Genome Res 27, 913-21)
  • Chromatin-bound oncoprotein DEK as gate-keeper of chromatin (Ivanauskiene et al 2014 Genome Res 24, 1584-1594)
  • 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)