An enhancer RNA recruits KMT2A to regulate transcription of Myb

• Published in: Cell reports (Cambridge) Vol. 43; no. 7; p. 114378
• Main Authors: Kim, Juhyun, Diaz, Luis F., Miller, Matthew J., Leadem, Benjamin, Krivega, Ivan, Dean, Ann
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2024; Elsevier
• Subjects: CP: Molecular biology; enhancer hub; enhancer RNA; erythroid differentiation; gene expression; H3K4me3; KMT2A; lncRNA; MLL1; Myb; Pol II pause release; MLL1; enhancer hub; enhancer RNA; lncRNA; KMT2A; H3K4me3; Myb; CP: Molecular biology; Pol II pause release; gene expression; erythroid differentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114378

The Myb proto-oncogene encodes the transcription factor c-MYB, which is critical for hematopoiesis. Distant enhancers of Myb form a hub of interactions with the Myb promoter. We identified a long non-coding RNA (Myrlin) originating from the −81-kb murine Myb enhancer. Myrlin and Myb are coordinately regulated during erythroid differentiation. Myrlin TSS deletion using CRISPR-Cas9 reduced Myrlin and Myb expression and LDB1 complex occupancy at the Myb enhancers, compromising enhancer contacts and reducing RNA Pol II occupancy in the locus. In contrast, CRISPRi silencing of Myrlin left LDB1 and the Myb enhancer hub unperturbed, although Myrlin and Myb expressions were downregulated, decoupling transcription and chromatin looping. Myrlin interacts with the KMT2A/MLL1 complex. Myrlin CRISPRi compromised KMT2A occupancy in the Myb locus, decreasing CDK9 and RNA Pol II binding and resulting in Pol II pausing in the Myb first exon/intron. Thus, Myrlin directly participates in activating Myb transcription by recruiting KMT2A. [Display omitted] •Long non-coding RNA Myrlin is transcribed from the murine Myb −81-kb enhancer•CRISPRi of Myrlin separates Myb enhancer looping from transcription activation•Myrlin is necessary for KMT2A/MLL1 recruitment to Myb and for RNA Pol II pause release•Myrlin eRNA directly participates in activating Myb transcription Long non-coding RNA Myrlin is transcribed from the murine Myb −81-kb enhancer. Myb enhancer looping is unaffected by Myrlin CRISPRi, but Myb transcription is downregulated. Kim et al. found that Myrlin directly participates in transcription activation by recruiting KMT2A/MLL1 to Myb and allowing RNA Pol II pause release into elongation.