Abstract

The broad goal of this project is to develop a suite of chemistry-driven tools to study the detailed mechanism by which histone mutations associated with cancers dys-regulate chromatin states, leading to disease. We will focus our efforts on a set of H3 mutants linked to pediatric gliomas (H3K27M and H3G34R/V) and chondroblastomas (H3K36M). By combining the use of chemically-defined chromatin templates with biochemical, proteomic and genomic approaches, we seek to develop a sufficient body of knowledge around the H3 mutants such that logical paths to therapy can be conceived. As an example of this, we will explore the idea that the toxic effect of these mutants on methyltransferase activities can be neutralized by manipulation of other epigenetic modification pathways. We imagine that many of the technologies developed in the context of this project will have broad utility in the epigenetics field generally.

Public Health Relevance

The broad goal of this project is to develop a suite of chemistry-driven tools to study the detailed mechanism by which histone H3 mutations, oncohistones, associated with pediatric brain and bone cancers mis-regulate epigenetic control of gene expression, leading to disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA196539-04
Application #
9567097
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Simithy, Johayra; Sidoli, Simone; Garcia, Benjamin A (2018) Integrating Proteomics and Targeted Metabolomics to Understand Global Changes in Histone Modifications. Proteomics 18:e1700309
Di Marcantonio, Daniela; Martinez, Esteban; Sidoli, Simone et al. (2018) Protein Kinase C Epsilon Is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia. Clin Cancer Res 24:608-618
Valera, Elvis Terci; McConechy, Melissa K; Gayden, Tenzin et al. (2018) Methylome analysis and whole-exome sequencing reveal that brain tumors associated with encephalocraniocutaneous lipomatosis are midline pilocytic astrocytomas. Acta Neuropathol 136:657-660
Wojcik, Felix; Dann, Geoffrey P; Beh, Leslie Y et al. (2018) Functional crosstalk between histone H2B ubiquitylation and H2A modifications and variants. Nat Commun 9:1394
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:

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