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Folic acid deficiency in pregnant women increases the risk of developing NTDs; however, the underlying etiology and mechanisms remain elusive. In this study, the role of DNA double\u2010strand breaks (DSBs) in 3D genome organization in NTDs with folate deficiency is reported. The NTD mouse model is burdened with abundant DSBs associated with the disruption of 3D genome organization. DSBs occurring in active genes lead to the stalling of RNA polymerase II (Pol II) and formation of R\u2010loops in the 3D genome. The DSB ratios of the genomic regions negatively correlated with the distance from the transcription start sites of the gene. The DSB ratios of the proximal and distal enhancers are significantly higher and induce the displacement of loops with busy anchors. Furthermore, DSB\u2010associated dysregulation of chromatin loops occurs in neural tube closure\u2013associated genes that are abnormally expressed in human NTDs. Taken together, excessive DSB\u2010associated 3D genome organization disruption within NTDs with folate deficiency contributes to the dysregulation of neural tube closure\u2013associated genes.<\/jats:p>","DOI":"10.1002\/advs.202410603","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T18:21:52Z","timestamp":1758219712000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Excessive DNA Double\u2010Strand Breaks\u2013Associated 3D Genome Reorganization Contributes to Neural Tube Defects with Folate Deficiency"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6100-8327","authenticated-orcid":false,"given":"Ting","family":"Zhang","sequence":"first","affiliation":[{"name":"Capital Center for Children's Health Capital Medical University Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine  Beijing 100850 China"},{"name":"School of Computer Science and Information Technology&amp; KLAS Northeast Normal University  Beijing 100730 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology College of Basic Medicine Shanxi Key Laboratory of Birth Defect and Cell Regeneration MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention  Taiyuan 030001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caihua","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai GeneCowin Biotechnology Co. 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Shanghai 200120 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjun","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Children's and Adolescent Health Public Health College Harbin Medical University  Harbin 150081 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Bai","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine  Beijing 100850 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Capital Center for Children's Health Capital Medical University Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Bao","sequence":"additional","affiliation":[{"name":"Capital Center for Children's Health Capital Medical University Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Guo","sequence":"additional","affiliation":[{"name":"Center for Biomedical Technology Institute of Clinical Medicine Peking Union Medical College Hospital Chinese Academy of Medical Sciences  Beijing 100730 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Bo","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine  Beijing 100850 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine  Beijing 100850 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hebing","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine  Beijing 100850 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2980-7273","authenticated-orcid":false,"given":"Qiu","family":"Xie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100850 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21026"},{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1673-8527(08)60108-3"},{"key":"e_1_2_9_1_3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-062012-170354"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1181369"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.021"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.06.004"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.043"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.06.007"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2408"},{"key":"e_1_2_9_7_1","first-page":"1672","volume":"167","author":"Mirzazadeh R.","year":"2018","journal-title":"Methods Mol. 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