(ALLIS) Genome-wide sequencing technologies have allowed an unprecedented discovery of somatic mutations in chromatin and epigenetic modifiers in human cancers, providing mechanistic links between cancer epigenomes and genetic alterations. The collective number of oncogenic mutations in epigenetic regulators has led to the emerging view of ?driver mutations? underlying cancer epigenomes. Nowhere is this better illustrated than with the now classical findings of high-frequency (50-95%) missense mutations in core histones, such as histone H3 lysine 27 to methionine (H3K27M) mutation in pediatric gliomas, and H3 lysine 36 to methionine (H3K36M) mutations in chondroblastomas and undifferentiated sarcomas. During the prior grant period, we have shown that these mutations directly prevent the ?writing? of some critical regulatory histone post-translational modifications (PTMs) to promote oncogenesis through altered chromatin organization, transcription, and in some cases cell fate and differentiation. More recently, we have extended our understanding of the landscape of histone mutations in cancers. We characterized an unexpectedly broad landscape of novel oncohistone mutations that occur in roughly 4% of all cancers. These mutations are found not only in the H3 N-terminal tail, which is the site of classical oncohistones, but also in the globular domain and in all four core histones. Our preliminary data suggest that a least a subset of these mutations affect one or more properties of chromatin and chromatin-dependent processes including nucleosome stability, histone PTMs, and cellular differentiation. We therefore hypothesize that novel oncohistone mutations will impact the landscape of histone PTMs and chromatin organization in a context dependent manner, leading to dysregulation of gene expression and effects on cell fate and tumorigenesis. The goal of this work is to rigorously test these hypotheses for a comprehensive set of cancer-associated histone mutations using a multidisciplinary approach that include genetics (barcoded oncohistone libraries, mouse models, barcoded-cell lines), epigenetics (ChIP-seq, ATAC-seq, DNA-methylation profiling), transcriptomics (RNA-seq), and chemical biology (?designer chromatin?, small molecule inhibitors). Specifically, we will 1) define molecular mechanisms by which novel oncohistones act and their impact on chromatin and gene expression; 2) determine how these molecular changes translate into phenotypes using cellular differentiation and tumor allograft models, and explore pharmacologic strategies to rescue differentiation blockade; and 3) extend our studies into animal models and diverse cellular contexts to test the roles of novel oncohistones in tumorigenesis and development. Together, these approaches will shed light on the function of newly discovered oncohistones and provide important insight into the role of histones and chromatin structure in tumorigenesis. Our findings are expected to pave new avenues towards intervening pharmacologically the aberrant epigenetic pathways for cancer therapeutics. To facilitate the success of this proposal, a world-class team of investigators, experts in cancer, chromatin and chemical biology, have been assembled.
(ALLIS) Genome-wide sequencing technologies have allowed an unprecedented discovery of somatic mutations in ?chromatin and epigenetic modifiers? in human cancers, including high-frequency mutations in histones, the proteins charged with packaging our genome. The proposed research will determine how newly identified cancer-associated histone mutations disrupt epigenetic landscapes and lead to cancer. These findings are expected to pave new avenues for the development of cancer therapeutics in tumors harboring histone mutations.
|Lee, Chul-Hwan; Yu, Jia-Ray; Kumar, Sunil et al. (2018) Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin. Mol Cell 70:422-434.e6|
|Guo, Qi; Sidoli, Simone; Garcia, Benjamin A et al. (2018) Assessment of Quantification Precision of Histone Post-Translational Modifications by Using an Ion Trap and down To 50?000 Cells as Starting Material. J Proteome Res 17:234-242|
|Weiner, Amber K; Sidoli, Simone; Diskin, Sharon J et al. (2018) Graphical Interpretation and Analysis of Proteins and their Ontologies (GiaPronto): A One-Click Graph Visualization Software for Proteomics Data Sets. Mol Cell Proteomics 17:1426-1431|
|Gomes, Carolina Cavalieri; Gayden, Tenzin; Bajic, Andrea et al. (2018) TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw. Nat Commun 9:4572|
|Shastrula, Prashanth Krishna; Lund, Peder J; Garcia, Benjamin A et al. (2018) Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms. J Biol Chem 293:12360-12377|
|Bharathy, Narendra; Berlow, Noah E; Wang, Eric et al. (2018) The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. Sci Signal 11:|
|Lin-Shiao, Enrique; Lan, Yemin; Coradin, Mariel et al. (2018) KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. Genes Dev 32:181-193|
|Aebersold, Ruedi; Agar, Jeffrey N; Amster, I Jonathan et al. (2018) How many human proteoforms are there? Nat Chem Biol 14:206-214|
|Yuan, Zuo-Fei; Sidoli, Simone; Marchione, Dylan M et al. (2018) EpiProfile 2.0: A Computational Platform for Processing Epi-Proteomics Mass Spectrometry Data. J Proteome Res 17:2533-2541|
|Zhang, Hanghang; Pandey, Somnath; Travers, Meghan et al. (2018) Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. Cell 175:1244-1258.e26|
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