[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-452984-105":3,"doc-detail-452984-en":80,"detail-sidebar-cat-0-en-105":97},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":73,"head_meta":75,"extra_data":77,"updated_unix":79},105,"en","multimodal-bhlh-pas-dna-binding-controls-specificity-and-drives-obesity","Multimodal bHLH-PAS DNA binding controls specificity and drives obesity","","The basic-helix-loop-helix Per-Arnt-Sim (PAS) homology domain (bHLH-PAS) transcription factor family senses physiological and environmental cues to regulate gene programs governing signal adaptation and homeostasis. Mechanisms determining DNA-binding specificity and target regulation by this subfamily remain unclear. Systematic mapping of cognate DNA-binding hierarchies across prototypical members identifies large footprints and sequence-flanking rules that distinguish otherwise shared core motifs, linking DNA shape, PAS-loop interactions, and downstream SIM1 activity to hyperphagic obesity in a SIM1 R171H knock-in model.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/multimodal-bhlh-pas-dna-binding-controls-specificity-and-drives-obesity/452984/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/multimodal-bhlh-pas-dna-binding-controls-specificity-and-drives-obesity/452984.png","ImageObject",300,407,{"name":42,"@type":43},"Patrick","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-30","2026-09-30",true,{"@type":52,"interactionType":53,"userInteractionCount":26},"InteractionCounter",{"@type":54},"ViewAction",{"@type":56,"mainEntity":57},"FAQPage",[58,64,68],{"name":59,"@type":60,"acceptedAnswer":61},"What biological stimuli does the bHLH-PAS transcription factor family respond to?","Question",{"text":62,"@type":63},"It responds to physiological stimuli such as hypoxia, tryptophan metabolites, neuronal activity, and appetite signals, as well as environmental cues including diet-derived metabolites and pollutants.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"How was DNA-binding specificity analyzed in this study?",{"text":67,"@type":63},"The work systematically analyzed cognate DNA-binding hierarchies of prototypical bHLH-PAS members and identified large DNA footprints and distinct mechanisms involving preferential flanking sequences around the core motif.",{"name":69,"@type":60,"acceptedAnswer":70},"What is the role of SIM1 downstream interactions in obesity?",{"text":71,"@type":63},"Novel downstream SIM1 PAS-loop/DNA interactions associated with AT-rich sequences contribute to DNA binding and transcriptional activity, which is tied to a monogenic cause of human hyperphagic obesity modeled by SIM1 R171H knock-in mice.","https://schema.org",{"og:url":32,"og:type":74,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":76,"canonical":32},"index,follow",{"doc_id":78,"site_id":7},452984,1790738005,{"code":4,"msg":81,"data":82},"success",{"doc_id":78,"user_id":83,"nickname":42,"user_avatar":84,"doc_module":4,"category_id":85,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":86,"file_id":87,"file_url":88,"file_type":89,"file_size":90,"view_count":26,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":91,"language":92,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":93,"faqs":94,"seo_title":95,"seo_description":12,"update_tm":79,"read_time":96,"preview_page_count":4},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470",7,"Multimodal bHLH-PAS DNA binding controls specificity and drives obesity  \nDavid C. Bersten1,2 ,* , Daniel P. McDougal1,3 , Adrienne E. Sullivan1,4,5, Alexis Gerassimou 1 , James Breen2,6 , Rebecca L. Fitzsimmons7 , George EO Muscat7 , Stephen Pederson 6 , John B. Bruning 1,3 , Chen-Ming Fan8 , Paul Q. Thomas9 , Darryl L. Russell2 , Daniel J. Peet 1 ,  \nMurray L. Whitelaw 1,10 ,*  \n1The Department of Molecular and Biomedical Science, School of Biological Sciences, The University of Adelaide, Adelaide, SA 5001, Australia  \n2 Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA 5001, Australia  \n3 Institute for Photonics and Advanced Sensing, The University of Adelaide, Adelaide, SA 5001, Australia  \n4Adelaide Centre for Epigenetics, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5001, Australia  \n5 South Australian immunoGENomics Cancer Institute, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5001, Australia  \n6 Bioinformatics Hub, University of Adelaide, Adelaide, SA 5001, Australia  \n7 Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4067, Australia  \n8 Carnegie Institution for Science, Department of Embryology, Baltimore, MD 21218, United States  \n9 Gene Editing Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia  \n10ASEAN Microbiome Nutrition Centre, National Neuroscience Institute, Singapore 169857, Singapore  \n∗ To whom correspondence should be addressed. Email: [david.bersten@adelaide.edu.au](david.bersten@adelaide.edu.au)  \nCorrespondence may also be addressed [to Murray L. Whitelaw. Email:](to Murray L. Whitelaw. Email: murray.whitelaw@adelaide.edu.au)[ murray.whitelaw@adelaide.edu.au](to Murray L. Whitelaw. Email: murray.whitelaw@adelaide.edu.au)  \nAbstract  \nThe basic-helix-loop-helix Per-Arnt-Sim (PAS) homology domain (bHLH-PAS) transcription factor (TF) family comprises critical sensors or actuators of physiological (hypoxia, tryptophan metabolites, neuronal activity, and appetite) and environmental (diet-derived metabolites and pollutants) stimuli regulating genes involved in signal adaptation and homeostasis. Despite the importance of this TF family, the mechanisms underlying specificity of DNA binding and target gene regulation by the bHLH-PAS subfamily remain unresolved. We systematically analysed cognate DNA binding hierarchies of prototypical bHLH-PAS family members (ARNT, ARNT2, HIF1 α, HIF2 α, AhR, NPAS4, SIM1), revealing large DNA binding footprints (12–15 bp) and unique mechanisms of DNA binding specificity involving preferential DNA sequences flanking the core motif. Flankencoded DNA binding specificity discerns otherwise identical core sequence binding by SIM1 and the HIFs, mediated through N-terminal HIFα– DNA interactions. We also reveal an intimate relationship between DNA shape and core and flank TF binding that allows motif sequence flexibility and underpins multimodal mechanisms for achieving TF binding specificity. Furthermore, novel downstream SIM1 PAS-loop/DNA interactions are associated with AT-rich sequences contributing to DNA binding and transcriptional activity; these interactions are critical for TF biological function underpinning a monogenic cause of human hyperphagic obesity in a recapitulated SIM1. R171H knock-in mouse model.  \nGraphical abstract  \nReceived: August 7, 2024. Revised: October 30, 2025. Accepted: November 6, 2025 © The Author(s) 2026. Published by Oxford University Press.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.  \n2 Bersten et al.  \nIntroduction  \nGene regulation is me","cbCaiclZfSYiHYnO","https://ap.wps.com/l/cbCaiclZfSYiHYnO","pdf",5159367,21,"English","# Abstract\n## Introduction","[{\"question\":\"What biological stimuli does the bHLH-PAS transcription factor family respond to?\",\"answer\":\"It responds to physiological stimuli such as hypoxia, tryptophan metabolites, neuronal activity, and appetite signals, as well as environmental cues including diet-derived metabolites and pollutants.\"},{\"question\":\"How was DNA-binding specificity analyzed in this study?\",\"answer\":\"The work systematically analyzed cognate DNA-binding hierarchies of prototypical bHLH-PAS members and identified large DNA footprints and distinct mechanisms involving preferential flanking sequences around the core motif.\"},{\"question\":\"What is the role of SIM1 downstream interactions in obesity?\",\"answer\":\"Novel downstream SIM1 PAS-loop/DNA interactions associated with AT-rich sequences contribute to DNA binding and transcriptional activity, which is tied to a monogenic cause of human hyperphagic obesity modeled by SIM1 R171H knock-in mice.\"}]","Multimodal bHLH-PAS DNA binding controls specificity and drives obesity | PDF",53,{"code":4,"msg":81,"data":98},[99,103,107,111,116,121,124,129,134,137,141],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":100,"show_sort_weight":101,"slug":102},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":104,"show_sort_weight":105,"slug":106},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":108,"show_sort_weight":109,"slug":110},"Exam",70,"exam",{"id":112,"doc_module":4,"doc_module_name":25,"category_name":113,"show_sort_weight":114,"slug":115},5,"Comic",60,"comic",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":118,"show_sort_weight":119,"slug":120},6,"Technology",50,"technology",{"id":85,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":122,"slug":123},40,"healthcare",{"id":125,"doc_module":4,"doc_module_name":25,"category_name":126,"show_sort_weight":127,"slug":128},8,"Research & Report",30,"research-report",{"id":130,"doc_module":4,"doc_module_name":25,"category_name":131,"show_sort_weight":132,"slug":133},9,"Religion & Spirituality",20,"religion-spirituality",{"id":132,"doc_module":4,"doc_module_name":25,"category_name":135,"show_sort_weight":132,"slug":136},"World Cup","world-cup",{"id":138,"doc_module":4,"doc_module_name":25,"category_name":139,"show_sort_weight":138,"slug":140},10,"Lifestyle","lifestyle",{"id":142,"doc_module":4,"doc_module_name":25,"category_name":143,"show_sort_weight":112,"slug":144},19,"General","general"]