An enhancer RNA recruits MLL1 to regulate transcription ofMyb

Abstract

SUMMARYTheMybproto-oncogene encodes the transcription factor c-MYB, which is critical for hematopoiesis. Distant enhancers ofMybform a hub of interactions with theMybpromoter. We identified a long non-coding RNA (Myrlin) originating from the −81 kb murineMybenhancer.MyrlinandMybare coordinately regulated during erythroid differentiation.MyrlinTSS deletion using CRISPR/Cas9 reducedMyrlinandMybexpression and LDB1 complex occupancy at theMybenhancers, compromising enhancer contacts and reducing RNA Pol II occupancy in the locus. In contrast, CRISPRi silencing ofMyrlinleft LDB1 and theMybenhancer hub unperturbed, althoughMyrlinandMybexpression were downregulated, decoupling transcription and chromatin looping.Myrlininteracts with the MLL1 complex.MyrlinCRISPRi compromised MLL1 occupancy in theMyblocus, decreasing CDK9 and RNA Pol II binding and resulting in Pol II pausing in theMybfirst exon/intron. Thus,Myrlindirectly participates in activatingMybtranscription by recruiting MLL1.