Paper on H3.3 and chromatin

Ivanauskiene, K., Delbarre, E., McGhie, J.D., K√ľntziger, T., Wong, L.H., and Collas, P. The PML-associated protein DEK regulates the balance of H3.3 loading on chromatin and is important for telomere integrity. Genome Research. 24: 1584-94

 

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Model of regulation of loading of H3.3 on chromatin by DEK. (A) Outside telomeres, DEK prevents chromatin loading of non-nucleosomal H3.3, which is recruited to PML NBs by DAXX (Delbarre et al. 2013). Loss of DEK by siRNA relaxes DNA topology and promotes broad HIRA-dependent H3.3 deposition on chromosome arms (lower right) and DAXX/ATRX-dependent loading in H3K9me3- and CBX3-containing heterochromatin foci where PML NBs also aggregate (upper right). (B) At telomeres, DEK has been previously shown to be essential for anchoring of PML NBs and ATRX, enabling H3.3 loading, and this is required to preserve telomere chromatin integrity (Chang et al. 2013). Loss of DEK results in dislocation of PML NBs and ATRX, impairment of H3.3 loading, and in a fragile telomere phenotype marked by TERF1 spreading, telomere elongation and up-regulation of the TERRA long non-coding RNA. The mislocated PML/ATRX/H3.3 complex may be relocated to pericentric heterochromatin.

 Abstract

Histone variant H3.3 is deposited in chromatin at active sites, telomeres and pericentric heterochromatin by distinct chaperone, but the mechanisms of regulation and coordination of chaperone-mediated H3.3 loading remain largely unknown. We show here that the chromatin-associated oncoprotein DEK regulates differential HIRA- and DAAX/ATRX-dependent distribution of H3.3 on chromosomes in somatic cells and in embryonic stem cells. Live cell imaging studies show that non-nucleosomal H3.3 normally destined to PML nuclear bodies is re-routed to chromatin after depletion of DEK. This results in HIRA-dependent wide-spread chromatin deposition of H3.3, and H3.3 incorporation in foci of heterochromatin, in process requiring the DAXX/ATRX complex. In embryonic stem cells, loss of DEK leads to displacement of PML bodies and ATRX from telomeres, redistribution of H3.3 from telomeres to chromosome arms and pericentric heterochromatin, induction of a fragile telomere phenotype and telomere dysfunction. Our results indicate that DEK is required for proper loading of ATRX and H3.3 on telomeres and for telomeric chromatin architecture. We propose that DEK acts as a 'gate-keeper' of chromatin, controlling chromatin integrity by restricting broad access to H3.3 by dedicated chaperones. Our results also suggest that telomere stability relies on mechanisms ensuring proper histone supply and routing.

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