Jaya Krishnan
Imperial College London, UK
Title: HERNA1 antisense RNA inhibition reverses cardiac pathology and improves survival
Biography
Biography: Jaya Krishnan
Abstract
Recent efforts have identified a subclass of non-coding RNAs templated at genomic enhancers (eRNAs) with gene regulatory function. Due to their genomic position we postulated their function in modulating signal-dependent tissue-specific transcriptional responses. Here we identify HERNA1, a conserved hypoxia-inducible factor (HIF) activated, cardiac-specific e RNA that integrates myocardial hypoxia signaling to regulate expression of a nearby pro-hypertrophic gene cluster in humans and mice. Elevated HERNA1 expression correlates with hypertrophic cardiomyopathy, but inversely correlates with dilated cardiomyopathy in humans. Through gain and loss-of-function studies, we observe a requirement for HERNA1 in the development of stress-dependent hypertrophic cardiomyopathy and mechanistically, identify direct HERNA1 interaction at the promoters of its downstream targets. In vivo delivery of antisense oligonucleotides targeting HERNA1 reverses cardiac pathogenesis, inhibits heart failure progression and increases overall survival in animals. These data unveil a novel heart-specific stress-dependent eRNA pathway and unveils a new strategy for tissue/cell type-specific therapeutics.