ABSTRACT
The inability of adult human cardiomyocytes to proliferate is an obstacle to efficient cardiac regeneration after injury. Understanding the mechanisms that drive postnatal cardiomyocytes to switch to a non-regenerative state is therefore of great significance. Here we show that Arid1a, a subunit of the switching defective/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, suppresses postnatal cardiomyocyte proliferation while enhancing maturation. Genome-wide transcriptome and epigenome analyses revealed that Arid1a is required for the activation of a cardiomyocyte maturation gene program by promoting DNA access to transcription factors that drive cardiomyocyte maturation. Furthermore, we show that ARID1A directly binds and inhibits the proliferation-promoting transcriptional coactivators YAP and TAZ, indicating ARID1A sequesters YAP/TAZ from their DNA-binding partner TEAD. In ischemic heart disease, Arid1a expression is enhanced in cardiomyocytes of the border zone region. Inactivation of Arid1a after ischemic injury enhanced proliferation of border zone cardiomyocytes. Our study illuminates the pivotal role of Arid1a in cardiomyocyte maturation, and uncovers Arid1a as a crucial suppressor of cardiomyocyte proliferation.
Subject(s)
Myocytes, Cardiac , Signal Transduction , Humans , Myocytes, Cardiac/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , DNA/metabolism , Cell Proliferation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolismABSTRACT
Glucocorticoid stress hormones are powerful modulators of brain function and can affect mood and cognitive processes. The hippocampus is a prominent glucocorticoid target and expresses both the glucocorticoid receptor (GR: Nr3c1) and the mineralocorticoid receptor (MR: Nr3c2). These nuclear steroid receptors act as ligand-dependent transcription factors. Transcriptional effects of glucocorticoids have often been deduced from bulk mRNA measurements or spatially informed individual gene expression. However, only sparse data exists allowing insights on glucocorticoid-driven gene transcription at the cell type level. Here, we used publicly available single-cell RNA sequencing data to assess the cell-type specificity of GR and MR signaling in the adult mouse hippocampus. The data confirmed that Nr3c1 and Nr3c2 expression differs across neuronal and non-neuronal cell populations. We analyzed co-expression with sex hormones receptors, transcriptional coregulators, and receptors for neurotransmitters and neuropeptides. Our results provide insights in the cellular basis of previous bulk mRNA results and allow the formulation of more defined hypotheses on the effects of glucocorticoids on hippocampal function.
