Genetics Seminar: "Varying and Poisoning the 'Histone Code': A Role of the Histone Variant H3.3 in Human Cancers"
Much of our current research is currently centered on chromatin and its regulation though post-translational modification of conventional and variant histone proteins. Previous elegant studies by Henikoff, Almouzni and others renewed the chromatin field’s interest in a histone H3 family member known as H3.3. Unlike other non-centromeric H3 family members (H3.1 and H3.2), H3.3 was thought to be a ‘replacement’ H3 variant whose deposition occurred outside of S-phase, largely into ‘active’ chromatin. Moreover, it was generally believed that HIRA was responsible for controlling the localization of H3.3 at these loci. Recently, Allis and colleagues compared the genome-wide localization of H3.3 in the presence and absence of HIRA in undifferentiated and differentiated mouse embryonic stem cells. As expected, HIRA was found to be required for H3.3 localization at many active genes. However, even in the absence of HIRA, H3.3 was still present in many other specific areas of the genome, including transcription factor binding sites (TFBS), and unexpectedly, ‘silent’ loci, such as telomeres and pericentric heterochromatin. Several additional proteins were found to be associated with H3.3. two of them, ATRX, a X-linked mental retardation protein, and Daxx, an apoptosis-related factor, had not been previously linked to H3.3 biology. Using a combination of structural and biochemical assays, new insights have been gained into mechanistic insight into how the ATRX-Daxx complex is targeted to specific genomic loci, and how this complex carries out H3.3-selective recognition. A recent report (Jiao et al. 2011) indicates that the genes encoding subunits of the ATRX-Daxx chromatin-remodeling complex are frequently mutated in a sporadic, non-functional pancreatic cancers, known as PanNETs. We favor the view that ATRX-Daxx complex regulates gene expression pathways and maintain genome integrity primarily through specialized chromatin assembly pathways that involve the selective deposition and assembly of H3.3.
Suggested reading:
- Goldberg et al., (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678-691
- Banaszynski et al., (2010) Histone variants in metazoan development. Dev. Cell 19, 662-674
- Elsaesser, S.J., Allis, C.D. and Lewis, P.W., (2011) New epigenetic drivers of cancer. Science 331, 1145-1146
- Elsaesser, S.J. et al., (2012) Structural basis of recognition specificity for histone variant H3.3 by the tumor suppressor DAXX. Nature, submitted.
Speaker
- C. David Allis, PhDTri-Institutional Professor and the Joy and Jack Fishman Professor