cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer Independent
Year: 2017
Type: article
Abstract: Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression. Indeed, an annotated super-enhancer is dispensable for NEK6 overexpression and for maintaining the architecture of a B cell-specific regulatory hub. A CTCF cluster serves as a chromatin and architectural boundary to block communication of the NEK6 regulatory hub with neighboring genes. Our findings emphasize that validation of predicted cis-regulatory circuits and super-enhancers is needed to prioritize transcriptional control elements as therapeutic targets.
Source: Cell Reports
Institution: Washington University in St. Louis
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G1114310655, REGULATION OF OF GENOME ARCHITECTURE IN LYMPHOCYTES: OPPOSING TETHER AND BOUNDARY FUNCTIONS, CHROMATIN-BASED DISCOVERY AND FUNCTION OF NOVEL TCR REGULATORY ELEMENTS, TARGETING EPIGENOMIC SIGNATURES IN NON-HODGKIN LYMPHOMA FOR NOVEL THERAPEUTICS, Washington University Institute of Clinical and Translational Sciences, SEQUENCE-SPECIFIC CHROMATIN MODIFIERS; NOVEL PROTEIN THERAPEUTICS FOR B CELL LYMPHOMA, G9000115080, G9000319192, Cancer Center Support Grant
OpenAlex ID: W2602809797