Transcriptome reprogramming is central to cardiac hypertrophy and pathological remodeling. Recent advances in genomics have dramatically expanded the scope and function of the cardiac transcriptome to cover much beyond the coding genes to include many non-coding genes. In particular, a vast cohort of long non-coding RNAs (so called lncRNAs) have been identified in cardiac transcriptome, yet, much of their functions remain unexplored. In preliminary studies leading to this proposal, we discovered a novel cardiac-enriched lncRNA expressed in mouse, rat and human heart which is demonstrated to be essential to pressure overload-induced cardiac hypertrophy. Furthermore, we demonstrated that this lncRNA interacts specifically with the chromatin modifying complex PRC2 to modulate H3K27me2/3 levels on pathological genes in stressed heart, thus we named this lncRNA as Cardiac Hypertrophy Associated Epigenetic Regulator (Chaer). Most intriguingly, we found Chaer transiently interacts with PRC2 transient at the onset of hypertrophic stimulation in an mTOR dependent manner. This transient interaction appears to be important to the early onset but not the subsequent progression of cardiac hypertrophy and heart failure. Therefore, the Chaer-PRC2 interaction appears to be an early epigenetic check-point necessary for hypertrophic gene expression and remodeling in the heart. This discovery highlights two potentially very important roles for lncRNAs in transcription regulation: one as a molecular switch to link epigenetic modifiers with cellular stress signals, and another as a molecular chaperon to orchestrate target specificity in the context of specific tissues for ubiquitous epigenetic modifiers. To further establish this novel concept, we propose to vigorously investigate the mechanism of Chaer mediated cardiac gene regulation by achieving the following three specific aims:
Aim 1. To uncover the molecular basis for hypertrophic signal regulated interaction between Chaer and PRC2.
Aim 2. To investigate how Chaer interaction regulates Ezh2 function in response to hypertrophic stimulation.
Aim 3. To establish the functional impact of Chaer-PRC2 interaction on cardiac epigenetic modulation and transcriptome reprogramming during cardiac hypertrophy. Accomplishing these aims will fill a major gap in our current knowledge of epigenetic regulation in cardiac hypertrophy and advance our mechanistic understanding of inducible, locus-specific chromatin modification in heart cells.
This project will explore a novel gene that encodes no protein but modulates the genome at the level of the chromosome during the process of cardiac hypertrophy and heart failure. In addition to demonstrating the essential role of this non-coding gene to stress induced cardiac hypertrophy and heart failure, the proposal will address a fundamental question of how chromatin is regulated by pathological stress to enable specific gene regulation.