Pathological stimuli alter the transcriptional program of the heart, thereby contributing to the pathogenesis of cardiac hypertrophy and failure. This transcriptional program is profoundly influenced by chromatin structure, which changes dynamically in response to extracellular cues. Cardiac gene expression is also controlled by a set of key transcription factors, including GATA4, which is essential for cardiac hypertrophy. Chromatin structure regulates transcription factor binding to DNA, and conversely transcription factors recruit protein complexes that modify chromatin structure. However, little information is available about this complex interplay between chromatin structure and transcription factors, particularly in the context of cardiac gene expression and the pathogenesis of heart failure. We and others have shown that GATA4 is an essential regulator of adult heart function. In our preliminary data, we further show that the GATA4 cofactor FOG2 is essential for normal function of the adult heart, in part by maintaining the coronary vasculature. In addition, we demonstrate a novel interaction between GATA4 and the polycomb complex PRC2, which governs cellular differentiation and lineage commitment by catalyzing histone methylation. In this proposal, we test the broad hypothesis that GATA4- chromatin interactions regulate the transcription of GATA4 target genes in cardiac hypertrophy and failure, and these interactions are modulated by FOG2 and PRC2. We propose the following specific aims: (1). In a neonatal cardiomyocyte hypertrophy model, we test the hypothesis that hypertrophic stimulation alters GATA4 chromatin occupancy and induces GATA4-dependent changes in chromatin structure that drive altered gene expression in cardiac hypertrophy. (2). We identify genes regulated by FOG2-GATA4 that contribute to the heart failure phenotype of FOG2-deficient mice, and dissect molecular mechanisms by which FOG2 influences GATA4-dependent transcriptional of these genes. (3). We test the hypothesis that PRC2 is essential for cardiac hypertrophy and function, and investigate the functional significance of GATA4-PRC2 interaction in regulating cardiac growth and homeostasis.
These aims will provide novel insights into how cellular context regulates transcriptional activity through interactions between transcription factors and chromatin structure. This knowledge may lead to novel therapeutic approaches for heart failure.

Public Health Relevance

Heart failure is the leading cause of morbidity and mortality in industrialized nations. Current treatments can slow the progression of heart failure and reduce the symptoms, but cannot reverse its course. One of the main contributors to the progression of heart failure is altered gene expression. While research in the last 20 years has identified many key factors that control gene expression in the failing heart, little is known about how they work. Research is also beginning to show that the packaging of genetic material inside the cell profoundly influences gene expression. However, understanding of how the packaging responds to signals from outside the cell, such as increased workload, are not well understood. In this proposal, we study how one key regulator factor, GATA4, controls gene expression and how it modifies genetic packaging in response to the cell's environment. This knowledge may lead to improved therapies that can reverse gene expression changes and disease course in heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095712-02
Application #
8013611
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2010-01-15
Project End
2013-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$431,250
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhou, Pingzhu; Gu, Fei; Zhang, Lina et al. (2017) Mapping cell type-specific transcriptional enhancers using high affinity, lineage-specific Ep300 bioChIP-seq. Elife 6:
Ai, Shanshan; Peng, Yong; Li, Chen et al. (2017) EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent. Elife 6:
Huang, Zhan-Peng; Ding, Yan; Chen, Jinghai et al. (2016) Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy. Cardiovasc Res 112:543-554
Lin, Zhiqiang; Zhou, Pingzhu; von Gise, Alexander et al. (2015) Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ Res 116:35-45
Prendiville, Terence W; Guo, Haidong; Lin, Zhiqiang et al. (2015) Novel Roles of GATA4/6 in the Postnatal Heart Identified through Temporally Controlled, Cardiomyocyte-Specific Gene Inactivation by Adeno-Associated Virus Delivery of Cre Recombinase. PLoS One 10:e0128105
He, Aibin; Gu, Fei; Hu, Yong et al. (2014) Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease. Nat Commun 5:4907
Prendiville, Terence; Jay, Patrick Y; Pu, William T (2014) Insights into the genetic structure of congenital heart disease from human and murine studies on monogenic disorders. Cold Spring Harb Perspect Med 4:
Lin, Zhiqiang; Pu, William T (2014) Harnessing Hippo in the heart: Hippo/Yap signaling and applications to heart regeneration and rejuvenation. Stem Cell Res 13:571-81
Aronson, B E; Rabello Aronson, S; Berkhout, R P et al. (2014) GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27. Biochim Biophys Acta 1839:1273-82
Prendiville, Terence W; Ma, Qing; Lin, Zhiqiang et al. (2014) Ultrasound-guided transthoracic intramyocardial injection in mice. J Vis Exp :e51566

Showing the most recent 10 out of 30 publications