We and others recently identified mutations in histone 3 variants in a significant fraction of children and young adults with a deadly brain tumor and maiming bone cancers. This is a very new uncharted area in cancer that will benefit from improved understanding of disease biology and the design of accurate experimental models to recapitulate these epigenetic cancers as we aim to do in this project. Strikingly data we further acquired with other funding suggest these ?oncohistones? as we labeled them possibly arise during specific windows of normal organ development. Indeed, each mutation in a given H3 isoform has age, organ and anatomic location within an organ, specificities. There is added complexity in HGA as we showed requirement of distinct added genetic alterations that are also age, brain location and H3 variant specific. Oncohistones are a new major paradigm shift in the field of cancer, and limited knowledge exists on how they act in tumor formation. Our project, integrated with other projects in this Program, aims to overcome this major knowledge gap and obstacle to effective therapy.
We aim to ?decode? how these mutations mechanistically affect the epigenomic landscape in tumors in the context of Development (Aims 1 and 2). We will provide critically needed relevant experimental models of histone mutations (Aim 2) and thrive to faithfully recapitulate human disease in HGA (Aims 2 and 3). Our group (Jabado/Majewski) was one of two to first identify a histone mutation in human disease. We have first-hand knowledge on HGA and other pediatric cancers and unparalleled access to tumor samples, animal models and clinical information. Allis identified H3.3 and the Allis and Muir labs are one of the best positioned to biochemically and mechanistically help study these mutations. There is natural synergy, cross-interactions and sharing of resources and materials between the three projects in this Program. We will receive essential support to integrate and analyse the vast datasets we are generating in primary tumors and model systems while benefiting from the resources and novel technical approaches and integration of complex datasets used by the Genomics/Epigenomics Sequencing core (Majewski and the epigenomic expert co- investigator Pastinen). The Quantitative proteomics core (Garcia), one of the rare groups able to study combination of mutations in histones on the protein level will allow precise measurement of histone mutants in patients and mouse samples and our experimental models. The natural interactions and synergies within this program and the level of expertise within it ensure that we will make significant breakthroughs in these cancers that can translate into improved care for patients.
We and others recently identified mutations in important guardians of our genetic information in a significant fraction of children and young adults with a deadly brain tumor and maiming bone cancers. These are known as histone 3 variants and are involved in regulating the development and growth of many body tissues, but particularly the brain, as we are now learning. This is a very new uncharted area in cancer that will benefit from improved understanding of disease biology and the design of accurate experimental models to recapitulate these epigenetic cancers as we aim to do in this project.
|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|
|Kreher, Jeremy; Takasaki, Teruaki; Cockrum, Chad et al. (2018) Distinct Roles of Two Histone Methyltransferases in Transmitting H3K36me3-Based Epigenetic Memory Across Generations in Caenorhabditis elegans. Genetics 210:969-982|
Showing the most recent 10 out of 63 publications