SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation

Abstract

Cardiac development requires coordinated and large-scale rearrangements of the epigenome. The roles and precise mechanisms through which specific epigenetic modifying enzymes control cardiac lineage specification, however, remain unclear. Here we show that the H3K4 methyltransferase SETD7 controls cardiac differentiation by reading H3K36 marks independently of its enzymatic activity. Through chromatin immunoprecipitation sequencing (ChIP-seq), we found that SETD7 targets distinct sets of genes to drive their stage-specific expression during cardiomyocyte differentiation. SETD7 associates with different co-factors at these stages, including SWI/SNF chromatin-remodeling factors during mesodermal formation and the transcription factor NKX2.5 in cardiac progenitors to drive their differentiation. Further analyses revealed that SETD7 binds methylated H3K36 in the bodies of its target genes to facilitate RNA polymerase II (Pol II)-dependent transcription. Moreover, abnormal SETD7 expression impairs functional attributes of terminally differentiated cardiomyocytes. Together, these results reveal how SETD7 acts at sequential steps in cardiac lineage commitment, and they provide insights into crosstalk between dynamic epigenetic marks and chromatin-modifying enzymes.

Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

“…We generated multiple patient-specific iPSC lines using non-integrating reprogramming methods 7,8 and derived iPSC-CMs using a chemically-defined protocol [8][9][10] to examine the electrophysiological properties at the single cell level. We found that the LMNA-mutant iPSC-CMs (III-3, III-9, III-15, and III-17) exhibited arrhythmias resembling delayed afterdepolarizations (DADs) in both atrial-and ventricular-like iPSC-CMs when compared to healthy controls (IV-1 and IV-2) ( Fig.…”

Functions of SETD7 during development, homeostasis and cancer

“…In other cases, SETD7-mediated methylation facilitates recruitment of transcription factors to chromatin (9,10). Finally, methylation of proteins by SETD7 affects protein-protein interaction both in the nucleus and cytoplasm (7,11,12). SETD7 is absent in pluripotent ESCs (11).…”

“…Finally, methylation of proteins by SETD7 affects protein-protein interaction both in the nucleus and cytoplasm (7,11,12). SETD7 is absent in pluripotent ESCs (11). Its expression is activated once cells transit from pluripotent to multipotent state and further maintained in post-mitotic differentiated cells (11).…”

“…SETD7 is absent in pluripotent ESCs (11). Its expression is activated once cells transit from pluripotent to multipotent state and further maintained in post-mitotic differentiated cells (11). Interestingly, the expression of SETD7 is lost in epithelial tumours (13,14).…”

SETD7 at the heart of chromatin factor interplay

“…The epigenetic enzyme regulation of the chromatin patterns in cardiac differentiation has been intensely investigated. New study in Cell Stem Cell highlights the role of lysine methyltransferase SETD7 in CM transcriptional programs (2). The authors' observations on striking upregulation of SETD7 upon differentiation of human embryonic stem cell (hESC) to mesodermal progenitors (MES), CM progenitors (CP) and CMs has prompted in depth investigation of the function of this enzyme.…”