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Cell Rep DOI:10.1016/j.celrep.2020.108426

Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression.

Publication TypeJournal Article
Year of Publication2020
AuthorsLin, L, Holmes, B, Shen, MW, Kammeron, D, Geijsen, N, Gifford, DK, Sherwood, RI
JournalCell Rep
Date Published2020 Nov 24

Gene expression is controlled by the collective binding of transcription factors to cis-regulatory regions. Deciphering gene-centered regulatory networks is vital to understanding and controlling gene misexpression in human disease; however, systematic approaches to uncovering regulatory networks have been lacking. Here we present high-throughput interrogation of gene-centered activation networks (HIGAN), a pipeline that employs a suite of multifaceted genomic approaches to connect upstream signaling inputs, trans-acting TFs, and cis-regulatory elements. We apply HIGAN to understand the aberrant activation of the cytidine deaminase APOBEC3B, an intrinsic source of cancer hypermutation. We reveal that nuclear factor κB (NF-κB) and AP-1 pathways are the most salient trans-acting inputs, with minor roles for other inflammatory pathways. We identify a cis-regulatory architecture dominated by a major intronic enhancer that requires coordinated NF-κB and AP-1 activity with secondary inputs from distal regulatory regions. Our data demonstrate how integration of cis and trans genomic screening platforms provides a paradigm for building gene-centered regulatory networks.


Alternate JournalCell Rep
PubMed ID33238122
PubMed Central IDPMC7724632
Grant ListR01 NS109217 / NS / NINDS NIH HHS / United States
R21 OD025309 / OD / NIH HHS / United States
R01 HG008363 / HG / NHGRI NIH HHS / United States
R01 HG008754 / HG / NHGRI NIH HHS / United States
R21 HG010391 / HG / NHGRI NIH HHS / United States
K01 DK101684 / DK / NIDDK NIH HHS / United States