cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer Independent.
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.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Yue
Y
Huang
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Olivia I
OI
Koues
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jiang-Yang
JY
Zhao
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Regina
R
Liu
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sarah C
SC
Pyfrom
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: jpayton@wustl.edu.
Jacqueline E
JE
Payton
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: eoltz@wustl.edu.
Eugene M
EM
Oltz
D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D000076246:CCCTC-Binding Factor / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019169:Jurkat Cells; D008224:Lymphoma, Follicular / Q000235:genetics / Q000473:pathology; D000072379:NIMA-Related Kinases / Q000235:genetics / Q000378:metabolism
D000076246:CCCTC-Binding Factor; D002843:Chromatin; C459456:NEK6 protein, human; D000072379:NIMA-Related Kinases
B cell lymphoma; NEK6; chromatin; chromosomal architecture; cis-regulatory circuits; gene regulation; super-enhancer