Genome-wide analysis of primary microRNA expression using H3K36me3 ChIP-seq data

MicroRNAs are key players in gene regulatory networks controlling cell homeostasis. Their altered expression has been previously linked to disease outcomes and microRNAs thus serve as biomarkers for disease diagnostics. However, their synthesis and its transcriptional regulation have been challenging to investigate. In this study, we validated the use of H3K36me3 histone modification for the quantification of microRNA transcription levels using data from the ENCODE Consortium and then applied this approach to provide new insight into the cell-type-specific regulation in tissues, cell line models and cardiac disease. In cardiomyocytes derived from patients suffering from septal defects, carrying a G296S mutation in the transcription factor GATA4, we show that microRNA gene transcription is altered in cardiomyocytes carrying this mutation and coincides with novel super-enhancers formed within regulatory domains defined using chromatin interaction profiles. The most prominently elevated primary transcript encodes for let-7a and miR-100 that may target genes in the Hippo signaling pathway. Collectively, our work presents a methodology to quantify microRNA gene expression using histone marker data and paves the way for functional studies of cell-type-specific transcriptional regulation occurring in disease pathology.