Over the past 25 years, genetic studies in model systems, such as mouse, have revealed highly conserved transcription factors (TFs) controlling human embryonic heart development. Although these studies have identified causal mutations that contribute to congenital heart defects (CHD), we still do not know the molecular causes associated with >80% of cases. Chromatin modulation acts to coordinate developmental signals and TF activity, and disruption of chromatin structure is emerging as a major contributor to CHD, yet its roles are least understood. This gap in our knowledge hinders our understanding of heart development and CHD, slowing the development of breakthrough drugs to treat these devastating malformations. Our proposal integrates innovative experimental and computational approaches to test the hypothesis that H2A.Z incorporation by specific ATP-dependent remodeling complexes regulates critical cardiac gene ciruits during lineage commitment. Notably, H2A.Z as well as components of its cognate remodeling complexes have been linked to heart development and disease, however, their roles are poorly understood. Our extensive preliminary work demonstrates that H2A.Z is enriched at promoter nucleosomes and acts as a molecular rheostat to control transcriptional output by coordinating with histone ?readers? and ?writers?, supporting our goal to dissect how these pathways functionally coordinate to regulate cardiac lineage commitment. Thus, we expect that the impact of this proposal is several fold: 1) Dissecting how H2A.Z dynamics regulates cardiac gene circuits represents a novel pathway for understanding how chromatin coordinates cardiac gene regulatory networks. 2) Our approach will contribute new tools and insights into the pathways that are disrupted in congenital heart defects (CHD). 3) Transcriptional control of embryonic heart development shares many features with induction of pathological gene expression in response to injury or disease, thus, our study opens the door for identifying potential new therapeutic targets for both CHD as well as pathological cardiac hypertrophy. 4) Our proposed aims will generate large-scale, genomic data in mouse cardiac cell types that can be immediately leveraged by the scientific community to enable additional discoveries. Finally, 5) the recent association of genetic variants within conserved genes coding for Chromatin Remodelers in patients with congenital and acquired heart defects indicates that our work will most certainly impact human health.

Public Health Relevance

Faulty regulation of gene expression programs underpins congenital heart disease and pathological heart failure. The proposed research is highly relevant to the NHLBI mission because it seeks to dissect the fundamental transcriptional and chromatin-mediated mechanisms regulating heart development, and to the NIH mission to enable new clinical strategies that will reduce the burden of human disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL140471-01
Application #
9439380
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2018-02-01
Project End
2022-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142