{"doi":"10.1016/j.stem.2019.03.022","title":"Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers","abstract":null,"journal":"Cell Stem Cell","year":2019,"id":636953,"datarank":0.6980940525236285,"base_score":4.653960350157523,"endowment":4.653960350157523,"self_citation_contribution":0.6980940525236285,"citation_network_contribution":0.0,"self_endowment_contribution":0.6980940525236285,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":104,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":251123,"name":"Zhaoning Wang","orcid":"0000-0002-0290-4746","position":1,"is_corresponding":false},{"id":672133,"name":"Glynnis A. Garry","orcid":"0000-0002-3777-0151","position":2,"is_corresponding":false},{"id":22174,"name":"Venkat S. Malladi","orcid":"0000-0002-0144-0564","position":3,"is_corresponding":false},{"id":325218,"name":"Giovanni A. Botten","orcid":"0000-0001-8054-8030","position":4,"is_corresponding":false},{"id":1653599,"name":"Wenduo Ye","orcid":null,"position":5,"is_corresponding":false},{"id":1354347,"name":"Huanyu Zhou","orcid":"0000-0003-3303-7312","position":6,"is_corresponding":false},{"id":251102,"name":"Marco Osterwalder","orcid":"0000-0002-1969-2313","position":7,"is_corresponding":false},{"id":37345,"name":"Diane E. Dickel","orcid":"0000-0001-5497-6824","position":8,"is_corresponding":false},{"id":43190,"name":"Axel Visel","orcid":"0000-0002-4130-7784","position":9,"is_corresponding":false},{"id":356007,"name":"Ning Liu","orcid":"0000-0001-5499-5849","position":10,"is_corresponding":false},{"id":807532,"name":"Rhonda Bassel-Duby","orcid":null,"position":11,"is_corresponding":false},{"id":225271,"name":"Eric N. Olson","orcid":"0000-0003-1151-8262","position":12,"is_corresponding":false},{"id":1364796,"name":"Hisayuki Hashimoto","orcid":"0000-0001-7367-4805","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers","abstract":"The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements. Intriguingly, these enhancer landscapes collectively resemble patterns of enhancer activation during embryonic cardiogenesis. We further constructed a cardiac reprogramming gene regulatory network and found repression of EGFR signaling pathway genes. Consistently, chemical inhibition of EGFR signaling augmented reprogramming. Thus, by defining epigenetic landscapes these findings reveal synergistic transcriptional activation across a broad landscape of cardiac enhancers and key signaling pathways that govern iCLM reprogramming.","is_dataset_classified":null,"base_score":4.653960350157523,"endowment":4.653960350157523,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31080136","pmcid":"PMC6754266","openalex_id":"https://openalex.org/W2944794345","authors":[],"funders":[{"funder_name":"NIAMS NIH HHS","grant_id":"R01 AR067294","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL130253","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R24 HL123879","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"T32 HL125247","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL138426","title":null},{"funder_name":"National Institutes of Health","grant_id":"5T32HL125247-04","title":"Training in Cardiovascular Research"},{"funder_name":"National Institutes of Health","grant_id":"5R24HL123879-02","title":"Genome-Wide Resources for Transcriptional Enhancers Active in the Human Heart"},{"funder_name":"National Institutes of Health","grant_id":"5R01HL138426-03","title":"Chemically assisted remodeling of infarcted heart tissue by targeting Wnt lipidation"},{"funder_name":"National Institutes of Health","grant_id":"5R01AR067294-02","title":"Molecular Dissection of Myoblast Fusion In Muscle Development and Regeneration"},{"funder_name":"National Institutes of Health","grant_id":"5R01HL130253-06","title":"Deciphering the role of a novel micropeptide in cardiac function and dysfunction"},{"funder_name":"Welch Foundation","grant_id":"","title":null},{"funder_name":"National Institute for Health Research (NIHR)","grant_id":"","title":null},{"funder_name":"Fondation Leducq","grant_id":"","title":null},{"funder_name":"Uehara Memorial Foundation","grant_id":"","title":null},{"funder_name":"Cancer Prevention and Research Institute of Texas","grant_id":"","title":null}],"total_grants":15,"fwci":4.4789,"citation_percentile":0.95885078,"influential_citations":0,"citation_trend":[{"year":2019,"count":4},{"year":2020,"count":15},{"year":2021,"count":24},{"year":2022,"count":16},{"year":2023,"count":15},{"year":2024,"count":11},{"year":2025,"count":11},{"year":2026,"count":8}],"oa_status":"green","license":"Elsevier Non-Commercial","oa_locations":[{"url":"https://escholarship.org/content/qt8fc904f9/qt8fc904f9.pdf","host_type":"repository"},{"url":"https://escholarship.org/content/qt8fc904f9/qt8fc904f9.pdf","host_type":"repository"},{"url":"https://api.elsevier.com/content/article/PII:S1934590919301213?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S1934590919301213?httpAccept=text/plain","host_type":"publisher"},{"url":"https://escholarship.org/uc/item/8fc904f9","host_type":"repository"},{"url":"https://doi.org/10.1016/j.stem.2019.03.022","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31080136","host_type":"repository"},{"url":"https://www.osti.gov/biblio/1650065","host_type":"repository"},{"url":"https://escholarship.org/uc/item/6vw8p091","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6754266","host_type":"repository"},{"url":"http://www.cell.com/article/S1934590919301213/pdf","host_type":""},{"url":"https://dx.doi.org/10.1016/j.stem.2019.03.022","host_type":""},{"url":"https://doi.org/https://doi.org/10.1016/j.stem.2019.03.022","host_type":""}],"fields_of_study":["Pluripotent Stem Cells Research","Congenital heart defects research","CRISPR and Genetic Engineering","0301 basic medicine","03 medical and health sciences","0303 health sciences","Animals","Basic Helix-Loop-Helix Proteins","Cells, Cultured","Cellular Reprogramming","ErbB Receptors","Fibroblasts","GATA4 Transcription Factor","Gene Regulatory Networks","Genome-Wide Association Study","MEF2 Transcription Factors","Mice","Mice, Inbred C57BL","Myocytes, Cardiac","Signal Transduction","T-Box Domain Proteins"],"mesh_terms":["Animals","Cells, Cultured","Fibroblasts","Mice, Inbred C57BL","Signal Transduction","T-Box Domain Proteins","Myocytes, Cardiac","GATA4 Transcription Factor","Mice","Basic Helix-Loop-Helix Transcription Factors","Basic Helix-Loop-Helix Proteins","Gene Regulatory Networks","Genome-Wide Association Study","MEF2 Transcription Factors","Cellular Reprogramming","ErbB Receptors"],"keywords":["MEF2C","Reprogramming","Enhancer","Biology","Transcription factor","Mef2","Cell biology","Epigenetics","Induced pluripotent stem cell","Embryonic stem cell","Regulation of gene expression","GATA4","Genetics","Gene","Computational biology","Cardiomyocytes","Heart regeneration","Akt1","Direct Reprogramming","Hand2","Tbx5","Induced Cardiac-like Myocytes","Basic Helix-Loop-Helix Proteins","570","Biomedical and clinical sciences","1.1 Normal biological development and functioning","Cells","610","Inbred C57BL","Cardiovascular","Medical and Health Sciences","Mice","Basic Helix-Loop-Helix Transcription Factors","2.1 Biological and endogenous factors","Animals","Gene Regulatory Networks","Myocytes, Cardiac","Cells, Cultured","Myocytes","Cultured","MEF2 Transcription Factors","Human Genome","Biological Sciences","Fibroblasts","Cellular Reprogramming","GATA4 Transcription Factor","ErbB Receptors","Mice, Inbred C57BL","Heart Disease","T-Box Domain Proteins","Cardiac","Developmental Biology","Genome-Wide Association Study","Signal 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