{"doi":"10.1242/dev.117838","title":"Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells","abstract":"<jats:p>The transcription factor brachyury (T, BRA) is one of the first markers of gastrulation and lineage specification in vertebrates. Despite its wide use and importance in stem cell and developmental biology, its functional genomic targets in human cells are largely unknown. Here, we use differentiating human embryonic stem cells to study the role of BRA in activin A-induced endoderm and BMP4-induced mesoderm progenitors. We show that BRA has distinct genome-wide binding landscapes in these two cell populations, and that BRA interacts and collaborates with SMAD1 or SMAD2/3 signalling to regulate the expression of its target genes in a cell-specific manner. Importantly, by manipulating the levels of BRA in cells exposed to different signalling environments, we demonstrate that BRA is essential for mesoderm but not for endoderm formation. Together, our data illuminate the function of BRA in the context of human embryonic development and show that the regulatory role of BRA is context dependent. Our study reinforces the importance of analysing the functions of a transcription factor in different cellular and signalling environments.</jats:p>","journal":"Development","year":2015,"id":669535,"datarank":0.7703697655575394,"base_score":5.135798437050262,"endowment":5.135798437050262,"self_citation_contribution":0.7703697655575394,"citation_network_contribution":0.0,"self_endowment_contribution":0.7703697655575394,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":169,"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":1748633,"name":"Andreia S. 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We show that BRA has distinct genome-wide binding landscapes in these two cell populations, and that BRA interacts and collaborates with SMAD1 or SMAD2/3 signalling to regulate the expression of its target genes in a cell-specific manner. Importantly, by manipulating the levels of BRA in cells exposed to different signalling environments, we demonstrate that BRA is essential for mesoderm but not for endoderm formation. Together, our data illuminate the function of BRA in the context of human embryonic development and show that the regulatory role of BRA is context dependent. Our study reinforces the importance of analysing the functions of a transcription factor in different cellular and signalling environments.</jats:p>","is_dataset_classified":null,"base_score":5.135798437050262,"endowment":5.135798437050262,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"26015544","pmcid":"PMC4483767","openalex_id":"https://openalex.org/W2158486555","authors":[],"funders":[{"funder_name":"The Francis Crick Institute","grant_id":"10157","title":null},{"funder_name":"British Heart Foundation","grant_id":"FS/12/37/29516","title":null},{"funder_name":"Medical Research Council","grant_id":"G0600275","title":null},{"funder_name":"British Heart Foundation","grant_id":"FS/10/022/28262","title":null},{"funder_name":"Medical Research Council","grant_id":"G0800784","title":null},{"funder_name":"Wellcome Trust","grant_id":"97922","title":null},{"funder_name":"Medical Research Council","grant_id":"MC_U117597140","title":null},{"funder_name":"Medical Research Council","grant_id":"U117597140","title":null},{"funder_name":"Medical Research Council","grant_id":"G1000847","title":null},{"funder_name":"Wellcome Trust","grant_id":"unidentified","title":"unidentified"},{"funder_name":"Fundação para a Ciência e a Tecnologia, I.P.","grant_id":"SFRH/BD/39758/2007","title":"MESODERM FORMATION AND PLURIPOTENCY IN MAMMALIAN EMBRYONIC STEM CELLS: THE ROLE OF BRACHYURY"}],"total_grants":11,"fwci":6.3397,"citation_percentile":0.97398233,"influential_citations":0,"citation_trend":[{"year":2015,"count":2},{"year":2016,"count":11},{"year":2017,"count":16},{"year":2018,"count":17},{"year":2019,"count":8},{"year":2020,"count":14},{"year":2021,"count":22},{"year":2022,"count":25},{"year":2023,"count":14},{"year":2024,"count":21},{"year":2025,"count":17},{"year":2026,"count":2}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://dev.biologists.org/content/develop/142/12/2121.full.pdf","host_type":"journal"},{"url":"https://dev.biologists.org/content/develop/142/12/2121.full.pdf","host_type":"publisher"},{"url":"http://journals.biologists.com/dev/article-pdf/142/12/2121/1693246/dev117838.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1242/dev.117838","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/26015544","host_type":"repository"},{"url":"https://research-information.bris.ac.uk/en/publications/a54b4d7d-79d2-41fa-99f6-15c9f0801024","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4483767","host_type":"repository"},{"url":"https://figshare.com/articles/journal_contribution/Brachyury_and_SMAD_signalling_collaboratively_orchestrate_distinct_mesoderm_and_endoderm_gene_regulatory_networks_in_differentiating_human_embryonic_stem_cells/12681905","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC4483767","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1242/dev.117838","host_type":""},{"url":"https://dx.doi.org/10.1242/dev.117838","host_type":""},{"url":"https://doi.org/https://doi.org/10.1242/dev.117838","host_type":""}],"fields_of_study":["Pluripotent Stem Cells Research","Renal and related cancers","Congenital heart defects research","0301 basic medicine","03 medical and health sciences","0303 health sciences"],"mesh_terms":["Brachyury Protein","Animals","Cell Line","Endoderm","Fetal Proteins","Humans","Mesoderm","Mice, Transgenic","Gene Expression Regulation, Developmental","T-Box Domain Proteins","Mice","Smad1 Protein","Smad2 Protein","Smad3 Protein","Embryonic Stem Cells","Gastrulation","Bone Morphogenetic Protein 4","Neurogenesis"],"keywords":["Brachyury","Biology","Mesoderm","Endoderm","Gastrulation","Embryonic stem cell","Cell biology","NODAL","Nodal signaling","Stem cell","Germ layer","Ectoderm","Genetics","Induced pluripotent stem cell","Gene","Human","Embryonic stem cells","Smad","Gene Regulatory Networks","T-box","Fetal Proteins","570","Endoderm/cytology","Neurogenesis/physiology","Neurogenesis","Mice, Transgenic","612","Bone Morphogenetic Protein 4","Smad2 Protein","Transgenic","Gastrulation/physiology","Cell Line","Smad1 Protein","Mice","Animals","Humans","Developmental","Smad3 Protein","Fetal Proteins/metabolism","Brachyury Protein","Embryonic Stem Cells/cytology","Smad2 Protein/metabolism","Gene Expression Regulation, Developmental","Smad1 Protein/metabolism","Smad3 Protein/metabolism","Stem Cells and Regeneration","Gene Expression Regulation","Mesoderm/cytology","T-Box Domain Proteins/metabolism","Bone Morphogenetic Protein 4/metabolism","T-Box Domain Proteins"],"sdg_mappings":[{"sdg_number":2,"sdg_label":"2. 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