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Using TWIST1 BioID-proximity-labeling and network propagation analyses, we discovered and characterized a TWIST-chromatin regulatory module (TWIST1-CRM) in the neural crest cells (NCC). Combinatorial perturbation of core members of TWIST1-CRM: TWIST1, CHD7, CHD8, and WHSC1 in cell models and mouse embryos revealed that loss of the function of the regulatory module resulted in abnormal differentiation of NCCs and compromised craniofacial tissue patterning. Following NCC delamination, low level of TWIST1-CRM activity is instrumental to stabilize the early NCC signatures and migratory potential by repressing the neural stem cell programs. High level of TWIST1 module activity at later phases commits the cells to the ectomesenchyme. Our study further revealed the functional interdependency of TWIST1 and potential neurocristopathy factors in NCC development.<\/jats:p>","DOI":"10.7554\/elife.62873","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T15:40:22Z","timestamp":1612798822000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.62873","source":"Crossref","is-referenced-by-count":51,"title":["TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-0616","authenticated-orcid":true,"given":"Xiaochen","family":"Fan","sequence":"first","affiliation":[{"name":"Embryology Unit, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"},{"name":"The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V Pragathi","family":"Masamsetti","sequence":"additional","affiliation":[{"name":"Embryology Unit, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane QJ","family":"Sun","sequence":"additional","affiliation":[{"name":"Embryology Unit, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasper","family":"Engholm-Keller","sequence":"additional","affiliation":[{"name":"Synapse Proteomics Group, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Osteil","sequence":"additional","affiliation":[{"name":"Embryology Unit, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Studdert","sequence":"additional","affiliation":[{"name":"Embryology Unit, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7290-1217","authenticated-orcid":true,"given":"Mark E","family":"Graham","sequence":"additional","affiliation":[{"name":"Synapse Proteomics Group, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Fossat","sequence":"additional","affiliation":[{"name":"Embryology Unit, Children\u2019s Medical Research Institute, The University of Sydney, Sydney, Australia"},{"name":"The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, Sydney, 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