dc.contributor.author | Lin, Lin | |
dc.contributor.author | Holmes, Benjamin Ray | |
dc.contributor.author | Shen, Max Walt | |
dc.contributor.author | Gifford, David K | |
dc.date.accessioned | 2021-01-21T20:01:47Z | |
dc.date.available | 2021-01-21T20:01:47Z | |
dc.date.issued | 2020-11 | |
dc.date.submitted | 2020-10 | |
dc.identifier.issn | 2211-1247 | |
dc.identifier.uri | https://hdl.handle.net/1721.1/129497 | |
dc.description.abstract | 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. | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (Grants RO1HG008363, 1R01HG008754 and 1R01NS109217) | en_US |
dc.language.iso | en | |
dc.publisher | Elsevier BV | en_US |
dc.relation.isversionof | 10.1016/j.celrep.2020.108426 | en_US |
dc.rights | Creative Commons Attribution-NonCommercial-NoDerivs License | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.source | Elsevier | en_US |
dc.title | Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Lin, Lin et al. “Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression.” Cell reports, 33, 8 (November 2020): 108426 © 2020 The Author(s) | en_US |
dc.relation.journal | Cell reports | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2020-12-15T16:43:34Z | |
dspace.orderedauthors | Lin, L; Holmes, B; Shen, MW; Kammeron, D; Geijsen, N; Gifford, DK; Sherwood, RI | en_US |
dspace.date.submission | 2020-12-15T16:43:39Z | |
mit.journal.volume | 33 | en_US |
mit.journal.issue | 8 | en_US |
mit.license | PUBLISHER_CC | |
mit.metadata.status | Complete | |