Histone Modification Dynamics in Heart Failure

Heart failure, affecting more than five million Americans annually, is a progressive syndrome for which novel mechanistic insights are needed. Cardiac hypertrophy is a known precursor of heart failure and has been shown to involve re-activation of genes silenced during normal development. The Vondriska lab seeks to understand how global changes in chromatin structure can be coordinated to reprogram the fully differentiated adult cell, inducing massive changes in gene expression and reversion to a more primitive phenotype (R01 HL105699). They reason that well-orchestrated chromatin remodeling events—involving chromatin structural proteins, i.e. histones, themselves – must exist to facilitate cardiac gene expression and propose that diseases like heart failure involve deranged chromatin structure at the genomic scale.

One short-term goal of this DBP is to understand the composition of histone variants in the nucleus, the changes in these proteins during cardiac hypertrophy and the alterations in their PTMs that occur with onset of disease [27]. Using the platform developed in TR&D 4, we will analyze histones from a clinically-relevant mouse model of pressure overload-induced cardiac hypertrophy and failure [28]. The long-term goal of this DBP is to integrate these concepts (through TR&D 2 and TR&D 3) to understand how the changing protein makeup of the nucleus impinges on chromatin across the genome.

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