Duplin: A Novel A-Kinase Anchoring Protein

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DESCRIPTION (provided by applicant): Following injury to the heart, the myocardium undergoes adaptive changes including hypertrophy, changes in contractility, and altered signaling. This process of 'cardiac remodeling' can ultimately lead to heart failure (HF), which is estimated to affect two percent of Americans, risk for which rises significantly with age. Mortality five years post-diagnosis is between sixty and seventy percent. Changes in gene expression associated with remodeling result in an expression profile similar to the fetal gene program; therefore, understanding normal development of the heart may shed light on the role of fetal genes in the development of heart pathology. Protein Kinase A (PKA) is a cAMP-dependent protein kinase that phosphorylates multiple cellular targets, including a number of transcription factors. A-Kinase Anchoring Proteins (AKAPs) characteristically bind the regulatory II subunits (Rll) of the enzyme and localize PKA to specific substrates, resulting in localized signaling domains within the cell. Decreased PKA-dependent phosphorylation is associated with HF. Multiple overlapping clones of the nuclear protein duplin/chromodomain helicase binding protein 8 (Chd8) were recently isolated in phage display screening of human heart cDNA for PKA binding proteins. Duplin/Chd8 inhibits Wnt and STATS-mediated transcription in the embryonic mouse, and is required for chromatin insulation in conjunction with the transcription represser CTCF. Duplin/Chd8 has been characterized as a developmental protein, but is also expressed adult tissue. We hypothesize that duplin/Chd8 is a novel AKAP and that PKA bound to duplin/Chd8 modulates inhibition of the transcription factor STATS. This hypothesized function of duplin/Chd8 has relevance to the molecular processes underlying cardiac remodeling and HF. Lay Summary: Following myocardial injury, gene expression in the heart changes to mimic that observed in development; however, this adaptive response does not long sustain the injured organ, and this condition can quickly deteriorate into heart failure (HF). The cell signaling kinase protein kinase A (PKA) and the transcription factor STATS are both compromised in HF. This study will test the hypothesis that the nuclear protein duplin/Chd8 mediates PKA-dependent regulation of STATS, exploring a potential mechanism by which STATS regulation could go awry in the failing heart.