R01CA259365

Structure-Activity Relationships Governing Mammalian SWI/SNF Chromatin Remodeling Activity as a Function of Chromatin State - Project Summary

Recent whole-exome sequencing studies in human cancer and neurodevelopmental disorders have unmasked frequent mutations in genes encoding chromatin regulatory proteins. Specifically, genes encoding subunits of the mammalian SWI/SNF ATP-dependent chromatin remodeling complexes (also called MSWI/SNF or BAF complexes) are perturbed in over 20% of malignancies, underscoring their critical roles in the maintenance of timely and appropriate gene expression.

The mechanisms by which MSWI/SNF family complexes are targeted on chromatin and the features of the histone landscape that govern their activities remain unknown. Indeed, a systematic evaluation defining the contributions of specific histone landscape features to canonical BAF, PBAF, and non-canonical BAF complex targeting and activity would represent a significant advancement in the field at large.

Here we aim to:

(1) Determine the genome-wide targeting of distinct, final-form MSWI/SNF complexes in human cells and the impact of select cancer-associated complex perturbations;

(2) Define the in vitro nucleosome remodeling and ATPase activities of endogenously-purified MSWI/SNF subcomplexes, BAF, PBAF, and NCBAF, in wild-type (WT) and mutant states; and

(3) Determine the impact of core histone variants and histone tail modifications on MSWI/SNF complex nucleosome binding and activity.

Taken together, successful completion of these aims centered at the intersection of biochemistry, epigenetics, and cancer biology will constitute a highly timely series of advances in the field of chromatin biology. It will contribute important knowledge regarding the mechanism of targeting of MSWI/SNF complexes across a range of both normal and oncogenic states.

Given that a major impediment to the development of on-target modulatory agents of MSWI/SNF complexes lies in the lack of biological understanding of complex-specific targeting and functional regulation, the results of this proposal are likely to provide the basis for new approaches toward targeted disruption of MSWI/SNF-chromatin interactions.

Dana-Farber Cancer Institute

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Boston, Massachusetts 022155418 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 380% from $709,868 to $3,409,205.