Noncoding function of super enhancer derived mRNA in modulating neighboring gene expression and TAD interaction

Super enhancers are important regulators of gene expression that often overlap with protein-coding genes. However, it is unclear whether the overlapping protein-coding genes and the mRNA derived from them contribute to enhancer activity. Using an erythroid-specific super enhancer that overlaps the Cpox gene as a model, we found that Cpox mRNA has a non-coding function in regulating neighboring protein-coding genes, eRNA expression and TAD interactions. Depletion of Cpox mRNA leads to accumulation of H3K27me3 and release of p300 from the Cpox locus, activating an intra-TAD enhancer and gene expression. Additionally, we identified a head-to-tail interaction between the TAD boundary genes Cpox and Dcbld2 that is facilitated by a novel type of repressive loop anchored by p300 and PRC2/H3K27me3. Our results uncover a regulatory role for mRNA transcribed within a super enhancer context and provide insight into head-to-tail inter-gene interaction in the regulation of gene expression and oncogene activation.