Year: 2020
Type: article
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.
Source: Cell Reports
Institutions: Brigham and Women's Hospital, Royal Netherlands Academy of Arts and Sciences, Harvard University, Massachusetts Institute of Technology, MIT Computer Science and Artificial Intelligence Laboratory, Leiden University Medical Center, Hubrecht Institute for Developmental Biology and Stem Cell Research, Broad Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: National Science Foundation, American Cancer Society, Human Frontier Science Program, Universiteit Utrecht, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, Harvard Stem Cell Institute, Brigham Research Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: Graduate Training in Computational and Systems Biology, Predictive transcription factor modeling to program endodermal cell fates, Distal enhancers controlling motor neuron gene expression program, High-Throughput Native Context Mapping and Modeling of Regulatory DNA, Systematic unlocking of airway stem cell differentiation program, High-throughput methods for elucidating the control of chromatin accessibility, Correcting genetic disorders using predictable CRISPR/Cas9-induced exon skipping
OpenAlex ID: W3106984292