Identification of a silencer-like non-coding RNA transcribed from a region on the super-enhancer conferring B-cell lymphomagenesis

Super-enhancers (SEs) orchestrate lineage-specific transcriptional programs and are frequently co-opted in cancer to sustain oncogenic gene expression. However, the functional complexity of SE-derived non-coding RNAs in B-cell lymphoma remains poorly understood. Here, we identify a lymphoma-specific SE located between the RGS1 and RGS13 loci (RGS-SE) through integrative in silico analysis of diffuse large B-cell lymphoma (DLBCL) enhancer landscapes. CRISPR/Cas9-mediated deletion of RGS-SE markedly impaired proliferation of Burkitt lymphoma cells and suppressed xenograft tumor growth, establishing its oncogenic relevance. Capture Hi-C revealed physical interactions between RGS-SE and the promoters of both RGS1 and RGS13, indicating a cis-regulatory architecture. Unexpectedly, transcriptomic analyses demonstrated that RGS-SE deletion increased RGS1 expression while modestly affecting RGS13, suggesting non-canonical regulatory activity. We further identified an SE-derived non-coding RNA (RGS-ncRNA) whose site-specific induction suppressed RGS1 transcription, whereas CRISPR interference modestly de-repressed it. Chromatin profiling revealed enrichment of H3K27me3 and PRC2 components within the RGS-ncRNA-coding region, consistent with silencer-like properties. Collectively, our findings uncover an oncogenic SE-ncRNA axis that functions not only as a classical enhancer but also as a PRC2-associated repressive module, expanding the conceptual framework of SE biology.