Pathological stress induces transcriptional gene reprogramming in the heart muscle, leading to cardiac myopathy and heart failure. Such stress-induced gene reprogramming requires regulation at the chromatin level by chromatin-regulating factors. The activity of chromatin regulators can be modulated by an emerging class of RNAs-the long noncoding RNAs (lncRNAs), which are long RNA transcripts with low/no protein-coding potential. The role of lncRNAs in hypertrophy and heart failure, however, is essentially unknown. Most studies of lncRNAs are conducted in cell cultures or in yeast, and mouse genetic models are lacking. This program will focus on a new mouse genetic model to define the molecular function of a newly identified lncRNA in controlling cardiac gene expression, hypertrophy, and failure. Because RNAs can be chemically modified and delivered as a drug for therapy, the success of this program will lay down a foundation for designing new mechanism-based therapy for heart failure.
Aim 1 : Defining the in vivo regulation of an lncRNA in the heart. We will use transgenic and knockout technology of mouse genetics to define the genetic and molecular mechanisms by which this lncRNA expression is regulated in the heart. Methods also include immunostaining, western blot, quantitative PCR, chromatin immunoprecipitation (ChIP), and RNA immunoprecipitation (RNA-IP) analyses.
Aim 2 : Determining how this lncRNA interacts with chromatin-regulating factor in the heart. We will use molecular, cellular, and biochemical methods to determine the molecular mechanism by which the lncRNA controls the molecular functions of chromatin regulators in the hearts. The methods include RNA-IP, ChIP, quantitative PCR, electric mobility shift assays, episome-based reporter assays, and nucleosome assembly.
Aim 3 : Defining the function of human lncRNA-protein complex. We will use human heart tissues and iPS-derived heart cells to demonstrate the presence of lncRNA complex. Also, we will use molecular, cellular, and biochemical methods to define the function of human lncRNA complex. The methods include RNA-IP, ChIP analysis of small amount of tissues, quantitative PCR, electric mobility shift assays, episome-based reporter assays, and iPS-based technology.

Public Health Relevance

Cardiomyopathy and heart failure is the major cause of morbidity and mortality in our society. Aberrant gene expression in the diseased heart is a critical step toward the development of heart failure. This program will define a new layer of regulatory mechanism for cardiac gene expression, thus providing a mechanistic base for designing new treatment for heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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Yang, Jin; Feng, Xuhui; Zhou, Qiong et al. (2016) Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex. Proc Natl Acad Sci U S A 113:E5628-35
Han, Pei; Li, Wei; Yang, Jin et al. (2016) Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts. Biochim Biophys Acta 1863:1772-81
Chang, Ching-Pin; Han, Pei (2016) Epigenetic and lncRNA regulation of cardiac pathophysiology. Biochim Biophys Acta 1863:1767-71
Han, Pei; Chang, Ching-Pin (2015) Myheart hits the core of chromatin. Cell Cycle 14:787-8
Han, Pei; Chang, Ching-Pin (2015) Long non-coding RNA and chromatin remodeling. RNA Biol 12:1094-8
Devaux, Yvan; Zangrando, Jennifer; Schroen, Blanche et al. (2015) Long noncoding RNAs in cardiac development and ageing. Nat Rev Cardiol 12:415-25
Li, Wei; Lin, Chieh-Yu; Shang, Ching et al. (2014) Pbx1 activates Fgf10 in the mesenchyme of developing lungs. Genesis 52:399-407
Van Nostrand, Jeanine L; Brady, Colleen A; Jung, Heiyoun et al. (2014) Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature 514:228-32
Han, Pei; Li, Wei; Lin, Chiou-Hong et al. (2014) A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514:102-106