Investigating the role of super-enhancer RNAs underlying embryonic stem cell differentiation

Super-enhancer RNAs (seRNAs) are a kind of noncoding RNA transcribed from super-enhancer regions. The regulation mechanism and functional role of seRNAs are still unclear. Although super-enhancers play a critical role in the core transcriptional regulatory circuity of embryonic stem cell (ESC) differentiation, whether seRNAs have similar properties should be further investigated. We analyzed cap analysis gene expression sequencing (CAGE-seq) datasets collected during the differentiation of embryonic stem cells (ESCs) to cardiomyocytes to identify the seRNAs. A non-negative matrix factorization algorithm was applied to decompose the seRNA profiles and reveal two hidden stages during the ESC differentiation. We further identified 95 and 78 seRNAs associated with early- and late-stage ESC differentiation, respectively. We found that the binding sites of master regulators of ESC differentiation, including NANOG, FOXA2, and MYC, were significantly observed in the loci of the stage-specific seRNAs. Based on the investigation of genes coexpressed with seRNA, these stage-specific seRNAs might be involved in cardiac-related functions such as myofibril assembly and heart development and act in trans to regulate the co-expressed genes. In this study, we used a computational approach to demonstrate the possible role of seRNAs during ESC differentiation.