Genomic Landscapes of Cardiac Arrhythmia and Heart Regeneration
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Use of high-throughput sequencing technology has revolutionized our ability to study heart development and regeneration. However, extracting crucial information from large-scale datasets is challenging. Here we demonstrated using bioinformatics analysis to identify genetic features causing human cardiac arrhythmias, as well as key components of heart regeneration. Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. Previous work focused on Pitx2 developmental functions that predispose to atrial fibrillation. It is unknown whether Pitx2 has distinct postnatal functions. Furthermore, it is unclear whether the 4q25 locus directly controls the expression of Pitx2 via physical interaction that forms three-dimensional chromatin structure. Inactivating Pitx2 in the postnatal atrium, unstressed adult Pitx2 homozygous mutant mice display sinus node dysfunction, an atrial fibrillation risk factor in human patients. An integrated genomics approach revealed Pitx2 target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators. Importantly, many Pitx2 target genes have been implicated in human atrial fibrillation by genome wide association studies. Moreover, chromatin conformation capture sequencing (4C-Seq) demonstrated a direct interaction of Pitx2 promoters and atrial-fibrillation-associated region. The mammalian heart regenerates poorly, and damage commonly leads to heart failure. Hippo signaling is kinase cascade that regulates organ size during development and prevents adult mammalian cardiomyocyte regeneration by inhibiting the transcription factor Yap. To identify Yap target genes that are activated during cardiomyocyte renewal and regeneration, we performed Yap chromatin immunoprecipitation sequencing (ChIP-Seq) and mRNA expression profiling in Hippo-deficient mouse hearts. We found that Yap directly regulated genes encoding cell cycle progression proteins, as well genes encoding proteins that promote F-actin polymerization and link the actin cytoskeleton to the extracellular matrix. Border-zone cardiomyocytes of injured Hippo-deficient mouse hearts showed cellular protrusions, indicating cytoskeletal remodeling. Our findings, revealing an independent postnatal role of Pitx2 in arrhythmias, unveil direct Pitx2 target genes that include channel and calcium handling genes as well as genes that stabilize the intercalated disc in postnatal atrium. In the context of mammalian cardiomyocyte regeneration, in addition to activating cell cycle genes, Yap regulated genes enhance cytoskeletal remodeling and the cellular response to local mechanical microenvironment.
Zhang, Min (2015). Genomic Landscapes of Cardiac Arrhythmia and Heart Regeneration. Doctoral dissertation, Texas A & M University. Available electronically from