Noncoding function of super enhancer derived <i>Cpox</i> pre-mRNA in modulating neighbouring gene expression and chromatin interactions

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 RNA derived from them contribute to enhancer activity. Using an erythroid-specific super enhancer that overlaps the <i>Cpox</i> gene as a model, <i>Cpox</i> pre-mRNA is found to have a non-coding function in regulating neighbouring protein-coding genes, eRNA expression and TAD interactions. Depletion of <i>Cpox</i> pre-mRNA leads to accumulation of H3K27me3 and release of p300 from the <i>Cpox</i> locus, activating an intra-TAD enhancer and gene expression. Additionally, a head-to-tail interaction between the TAD boundary genes <i>Cpox</i> and <i>Dcbld2</i> is identified, facilitated by a novel type of repressive loop anchored by p300 and PRC2/H3K27me3. These results uncover a regulatory role for pre-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.