Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression
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 ha...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/129497 |
| _version_ | 1826193589820981248 |
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| author | Lin, Lin Holmes, Benjamin Ray Shen, Max Walt Gifford, David K |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Lin, Lin Holmes, Benjamin Ray Shen, Max Walt Gifford, David K |
| author_sort | Lin, Lin |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:41:31Z |
| format | Article |
| id | mit-1721.1/129497 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:41:31Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1294972024-06-25T23:52:57Z Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression Lin, Lin Holmes, Benjamin Ray Shen, Max Walt Gifford, David K Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Computational and Systems Biology Program Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science 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. National Institutes of Health (U.S.) (Grants RO1HG008363, 1R01HG008754 and 1R01NS109217) 2021-01-21T20:01:47Z 2021-01-21T20:01:47Z 2020-11 2020-10 2020-12-15T16:43:34Z Article http://purl.org/eprint/type/JournalArticle 2211-1247 https://hdl.handle.net/1721.1/129497 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 10.1016/j.celrep.2020.108426 Cell reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Lin, Lin Holmes, Benjamin Ray Shen, Max Walt Gifford, David K Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression |
| title | Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression |
| title_full | Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression |
| title_fullStr | Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression |
| title_full_unstemmed | Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression |
| title_short | Comprehensive Mapping of Key Regulatory Networks that Drive Oncogene Expression |
| title_sort | comprehensive mapping of key regulatory networks that drive oncogene expression |
| url | https://hdl.handle.net/1721.1/129497 |
| work_keys_str_mv | AT linlin comprehensivemappingofkeyregulatorynetworksthatdriveoncogeneexpression AT holmesbenjaminray comprehensivemappingofkeyregulatorynetworksthatdriveoncogeneexpression AT shenmaxwalt comprehensivemappingofkeyregulatorynetworksthatdriveoncogeneexpression AT gifforddavidk comprehensivemappingofkeyregulatorynetworksthatdriveoncogeneexpression |