{"doi":"10.1016/j.jcmgh.2020.08.005","title":"Identification of Transcription Factors Regulating SARS-CoV-2 Entry Genes in the Intestine","abstract":"Gastrointestinal symptoms of coronavirus disease 2019 (COVID-19), including diarrhea, nausea, and vomiting, are more common than previously thought. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) likely causes these symptoms by infecting the epithelial cells lining the gastrointestinal tract,1Lamers M.M. et al.Science. 2020; 369: 50-54Crossref PubMed Scopus (1077) Google Scholar with angiotensin I converting enzyme 2 (ACE2) functioning as the viral receptor2Yan R. et al.Science. 2020; 367: 1444-1448Crossref PubMed Scopus (3320) Google Scholar and transmembrane serine protease 2 (TMPRSS2) functioning in viral spike protein priming.3Hoffmann M. et al.Cell. 2020; 181: 271-280 e8Abstract Full Text Full Text PDF PubMed Scopus (12591) Google Scholar Du et al4Du M. et al.Gastroenterology. 2020; 158: 2298-2301 e7Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar recently reported that ACE2 not only is expressed in lung alveolar type II (AT2) cells but also highly expressed in absorptive enterocytes. However, the regulatory mechanisms and transcription factors driving expression of Ace2 and Tmprss2 remains unclear. Using epigenomic approaches and mouse genetic models, we identify 4 key transcriptional regulators (caudal-type homeobox 2 (CDX2), hepatocyte nuclear factor 4 (HNF4), Smad family member 4 (SMAD4), or GATA binding proteins) that bind to the loci of these genes, alter chromatin looping, shape epigenetic modifications, and, ultimately, show a dramatic impact on Ace2 and Tmprss2 gene expression upon transcription factor knockout. We began by investigating the expression of COVID-19–related host genes throughout the body. Chromatin accessibility and RNA transcript levels show a tissue-specific expression pattern for Ace2 and Tmprss2, with greatest expression observed in intestine, kidney, and lung tissues (Figure 1A and B and Supplementary Figure 1). Ace2 and Tmprss2 are expressed more robustly in isolated intestinal epithelium compared with the remaining subepithelium (Figure 1C). Temporally, transcript levels of Ace2 and Tmprss2 increase during embryonic development (Figure 1D and F). In the adult tissue, Ace2 transcripts are increased in the villus compared with the crypt (Figure 1E and F). We next focused on the epithelial cell populations expressing the SARS-CoV-2–related genes. single cell RNA sequencing analysis defined cell populations within crypt epithelium that express markers of stem, progenitor, and differentiating epithelial cells (Supplementary Figure 2A). Cells expressing canonic goblet, Paneth, tuft, enteroendocrine, or enterocyte lineage markers were each identified, as expected (Supplementary Figure 2B–F, respectively). Other transcripts are expressed more broadly throughout the epithelium (Supplementary Figure 2G). We found Ace2 expression to be enriched in cells co-expressing mature enterocyte markers, whereas Tmprss2 was expressed more broadly throughout the epithelium (Supplementary Figure 2H). We next examined how intestinal transcription factor regulatory networks impact the expression of genes important for SARS-CoV-2 infection. CDX2 is required for specification of the intestine during embryonic development,5Gao N. et al.Dev Cell. 2009; 16: 588-599Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar and in adult life is required for intestinal maturation and proper enterocyte function.6Verzi M.P. et al.Mol Cell Biol. 2011; 31: 2026-2039Crossref PubMed Scopus (84) Google Scholar HNF4 factors are required for maturation of the embryonic intestine,7Chen L. et al.Development. 2019; 146: dev179432Crossref PubMed Scopus (25) Google Scholar and work in conjunction with SMAD4 to promote expression of adult enterocyte genes.8Chen L. et al.Nat Genet. 2019; 51: 777-785Crossref PubMed Scopus (68) Google Scholar GATA family transcription factors are important for intestinal regionalization.9Thompson C.A. et al.Cell Mol Gastroenterol Hepatol. 2017; 3: 422-446Abstract Full ","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2020,"id":104159,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9663,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":507475,"name":"A. Marishta","orcid":null,"position":1,"is_corresponding":false},{"id":354500,"name":"Christopher E. Ellison","orcid":"0000-0002-0350-0962","position":2,"is_corresponding":false},{"id":241177,"name":"Michael P. Verzi","orcid":"0000-0003-4082-4330","position":3,"is_corresponding":false},{"id":506485,"name":"Lei Chen","orcid":"0000-0001-7812-508X","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-18T22:43:22.755723Z","pmid":"32810597","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}