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Project 2: Elucidating Mechanisms of Chromatin Dysregulation by Oncohistones

项目 2：阐明肿瘤组蛋白染色质失调的机制

基本信息

批准号：
10269905
负责人：
CHARLES DAVID ALLIS
金额：
$ 26.7万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-09 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269905
关键词：
ATAC-seq Affect Alleles Allografting Animal Model Bar Codes Biological Assay Biology Cancer Biology Cancer cell line Cell Differentiation process Cell Fate Control Cell Line Cell physiology Cells Cellular Structures ChIP-seq Characteristics Charge Chemicals Childhood Glioma Chondroblastoma Chromatin Chromatin Structure Collaborations Complementary DNA Cues DNA DNA Damage DNA Modification Process DNA Repair DNA methylation profiling Data Defect Development Epigenetic Process Frequencies Gene Expression Genetic Genetic Screening Genetic Transcription Genome Goals Grant Growth H3 K27M mutation Histone H3 Histones Human Knock-in Laboratories Lead Libraries Light Link Lysine Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Mediating Mesenchymal Stem Cells Methionine Missense Mutation Modeling Modification Molecular Mus Mutate Mutation N-terminal Nucleosomes Oncogenic Pathologic Pathway interactions Patients Pharmacology Phenotype Play Positioning Attribute Post-Translational Protein Processing Pre-Clinical Model Process Property Proteins Reader Recurrence Research Research Personnel Role Site Somatic Mutation Structure Tail Technology Testing Therapeutic Translating Transplantation Tumor Subtype Undifferentiated Variant Work Writing Xenograft procedure cancer cell cancer type cell type cellular transduction design driver mutation epigenome gain of function genome-wide histone methyltransferase histone modification in vivo insight interdisciplinary approach mouse model multidisciplinary novel oncohistone prevent programs response sarcoma self-renewal small molecule small molecule inhibitor success transcriptome sequencing transcriptomics translational approach tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY (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.

项目总结（allis）