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. Specific histone chaperones 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-causing H3.3 mutation is H3.3K27M, which results in global reduction of H3K27me3. Other H3.3 mutations include H3.3G34R which affects surrouding H3.3  modifications.

Ongoing research:

  • Mechanisms of deposition of H3.3 into chromatin
  • Role of H3.3 on  the definition and resolution of chromatin domains
  • Impact of H3.3 mutations on nuclear architecture in DIPGs

Recent findings:

  • 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)
  • Identfication of PML-Associated domains (PADs); PML regulates H3.3 deposition and is important for maintance of heterochromatin domains (Debarre et al 2017 Genome Res 27, 913-21)