A Muscle-Specific Enhancer RNA Mediates Cohesin Recruitment and Regulates Transcription In trans

The enhancer regions of the myogenic master regulator MyoD give rise to at least two enhancer RNAs. Core enhancer eRNA ((CE)eRNA) regulates transcription of the adjacent MyoD gene, whereas (DRR)eRNA affects expression of Myogenin in trans. We found that (DRR)eRNA is recruited at the Myogenin locus, where it colocalizes with Myogenin nascent transcripts. (DRR)eRNA associates with the cohesin complex, and this association correlates with its transactivating properties. Despite being expressed in undifferentiated cells, cohesin is not loaded on Myogenin until the cells start expressing (DRR)eRNA, which is then required for cohesin chromatin recruitment and maintenance. Functionally, depletion of either cohesin or (DRR)eRNA reduces chromatin accessibility, prevents Myogenin activation, and hinders muscle cell differentiation. Thus, (DRR)eRNA ensures spatially appropriate cohesin loading in trans to regulate gene expression.