Abstract IA02: Varying and poisoning the “Histone Code”: A role of the histone variant H3.3 in human cancers

The human genome is estimated to contain ~25,000 unique genes; the DNA sequence and chromosomal location of many of these genes (protein and RNA-encoding and noncoding RNAs) are becoming widely known. A central challenge facing the biomedical community is how to derive medically valuable knowledge about the function of these genes from the now-available DNA sequence data. Although every gene exists within every cell in the human body, only a small percentage of genes are activated in any given cell or tissue type. To manage this genetic information efficiently, nature has evolved a sophisticated system in eukaryotes that facilitates access to specific genes. This system relies on a DNA-histone protein complex called chromatin to efficiently package the genetic information that exists within each cell type, giving rise to “epigenomes.” This packaging system makes certain genes more readily accessible to transcription factors and other machinery that must engage our genetic template. Chromatin remodeling, the collection of: 1) ATP-dependent reconfiguration of nucleosomes, 2) the exchange of conventional or non-conventional (variant) histones and 3) the post-translational modification of histones, and the regulation of the enzymes responsible for adding or subtracting them, are poised to take center stage in the study of cancer in the current post-genomic or epigenomic era. 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 field9s 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, nonfunctional 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: 1. Goldberg et al., (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678-691 2. Banaszynski et al., (2010) Histone variants in metazoan development. Dev. Cell 19, 662-674 3. Elsaesser, S.J., Allis, C.D. and Lewis, P.W., (2011) New epigenetic drivers of cancer. Science 331, 1145-1146 4. Elsaesser, S.J. et al., (2012) Structural basis of recognition specificity for histone variant H3.3 by the tumor suppressor DAXX. Nature, submitted. Citation Format: C. David Allis. Varying and poisoning the “Histone Code”: A role of the histone variant H3.3 in human cancers. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA02.