The Accessible Chromatin Landscape of Murine and Human Cardiomyocyte Development

Cardiomyocytes undergo maturation during early postnatal development to acquire the post-mitotic phenotype. Recent studies suggest an epigenetic basis to postnatal cardiomyocyte maturation although the mechanisms remain poorly understood. Here, we use the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in combination with RNA-seq to define relationships between chromatin accessibility and transcription in isolated murine and human cardiomyocyte nuclei for the first time. Cardiomyocyte purity was confirmed through qPCR profiling of cardiac (Myh6 and Myh7) and non-cardiac markers (Col1a1, Col3a1, Itgam and Vwf). RNA-seq revealed coordinated repression of cell cycle genes in cardiomyocytes from P1 to P14 in mice and between mid-gestation (16-19 weeks) to childhood (0-10 years) in humans. Moreover, integration of RNA-seq and ATAC-seq data sets identified a subset of genes that were transcriptionally repressed and associated with compacted chromatin during cardiomyocyte maturation in both mice and humans. Transcription factor (TF) analyses demonstrated that these genes were highly enriched for targets of cell cycle regulatory transcription factors such as E2F4 and FOXM1. The current study provides new insights into the epigenetic regulation of cardiomyocyte maturation and reveals a previously unrecognised mechanism for cell cycle arrest involving chromatin compaction around cell cycle genes.