{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T04:46:23Z","timestamp":1773290783706,"version":"3.50.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Non-syndromic cleft lip and palate (NSCLP) is one of the most common congenital malformations with multifactorial etiology. Although long non-coding RNAs (lncRNAs) have been implicated in the development of lip and palate, their roles in NSCLP are not fully elucidated. This study aimed to investigate how dysregulated lncRNAs contribute to NSCLP. Using lncRNA sequencing, bioinformatics analysis, and clinical tissue sample detection, we identified that lncRNA ZFAS1 was significantly upregulated in NSCLP. The upregulation of ZFAS1 mediated by SP1 transcription factor (SP1) inhibited expression levels of Wnt family member 4 (<jats:italic>WNT4<\/jats:italic>) through the binding with CCCTC-binding factor (CTCF), subsequently inactivating the WNT\/\u03b2-catenin signaling pathway, which has been reported to play a significant role on the development of lip and palate. Moreover, <jats:italic>in vitro<\/jats:italic>, the overexpression of ZFAS1 inhibited cell proliferation and migration in human oral keratinocytes and human umbilical cord mesenchymal stem cells (HUC-MSCs) and also repressed chondrogenic differentiation of HUC-MSCs. <jats:italic>In vivo<\/jats:italic>, ZFAS1 suppressed cell proliferation and numbers of chondrocyte in the zebrafish ethmoid plate. In summary, these results indicated that ZFAS1 may be involved in NSCLP by affecting cell proliferation, migration, and chondrogenic differentiation through inactivating the WNT\/\u03b2-catenin signaling pathway.<\/jats:p>","DOI":"10.3389\/fcell.2021.662780","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T04:23:07Z","timestamp":1624940587000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["SP1-Mediated Upregulation of Long Noncoding RNA ZFAS1 Involved in Non-syndromic Cleft Lip and Palate via Inactivating WNT\/\u03b2-Catenin Signaling Pathway"],"prefix":"10.3389","volume":"9","author":[{"given":"Shiyu","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhonglin","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mujie","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teng","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bowen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peixuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuexin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuntao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1182\/blood-2017-06-788695","article-title":"Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis.","volume":"130","author":"Alvarez-Dominguez","year":"2017","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1261\/rna.2528811","article-title":"SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer.","volume":"17","author":"Askarian-Amiri","year":"2011","journal-title":"Rna"},{"key":"B3","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1242\/dev.128.8.1253","article-title":"Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development.","volume":"128","author":"Brault","year":"2001","journal-title":"Development"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1002\/term.2914","article-title":"Mesenchymal stem cells: cell therapy and regeneration potential.","volume":"13","author":"Brown","year":"2019","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3283","DOI":"10.1242\/dev.005132","article-title":"Wnt signaling mediates regional specification in the vertebrate face.","volume":"134","author":"Brugmann","year":"2007","journal-title":"Development"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0962-6","article-title":"SP1-induced lncRNA-ZFAS1 contributes to colorectal cancer progression via the miR-150-5p\/VEGFA axis.","volume":"9","author":"Chen","year":"2018","journal-title":"Cell Death Dis."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/cells8091015","article-title":"Long non-coding rna in the pathogenesis of cancers.","volume":"8","author":"Chi","year":"2019","journal-title":"Cells"},{"key":"B8","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: understanding genetic and environmental influences.","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1002\/dvdy.24566","article-title":"Zebrafish models of orofacial clefts.","volume":"246","author":"Duncan","year":"2017","journal-title":"Dev. Dyn."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.114.122945","article-title":"The role of CCCTC-binding factor (CTCF) in genomic imprinting, development, and reproduction.","volume":"91","author":"Franco","year":"2014","journal-title":"Biol Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1177\/0960327116651121","article-title":"LncRNA H19-mediated mouse cleft palate induced by all-trans retinoic acid.","volume":"36","author":"Gao","year":"2017","journal-title":"Hum. Exp. Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"513","DOI":"10.3892\/mmr.2019.10261","article-title":"Comprehensive analysis of differentially expressed profiles of non-coding RNAs in peripheral blood and ceRNA regulatory networks in non-syndromic orofacial clefts.","volume":"20","author":"Gao","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15657","article-title":"An integrative transcriptomic atlas of organogenesis in human embryos.","volume":"5","author":"Gerrard","year":"2016","journal-title":"Elife"},{"key":"B14","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.devcel.2012.12.012","article-title":"The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse.","volume":"24","author":"Grote","year":"2013","journal-title":"Dev. Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.fct.2013.02.003","article-title":"Dexamethasone alters epithelium proliferation and survival and suppresses Wnt\/\u03b2-catenin signaling in developing cleft palate.","volume":"56","author":"Hu","year":"","journal-title":"Food Chem. Toxicol."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.424","article-title":"Retinoic acid alters the proliferation and survival of the epithelium and mesenchyme and suppresses Wnt\/\u03b2-catenin signaling in developing cleft palate.","volume":"4","author":"Hu","year":"","journal-title":"Cell Death Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"26067","DOI":"10.1074\/jbc.M113.486175","article-title":"Ribosomal RNA gene transcription mediated by the master genome regulator protein CCCTC-binding factor (CTCF) is negatively regulated by the condensin complex.","volume":"288","author":"Huang","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/dvdy.20646","article-title":"Development of the upper lip: morphogenetic and molecular mechanisms.","volume":"235","author":"Jiang","year":"2006","journal-title":"Dev. Dyn."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00264","article-title":"Canonical WNT\/\u03b2-Catenin Signaling Activated by WNT9b and RSPO2 cooperation regulates facial morphogenesis in mice.","volume":"8","author":"Jin","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1177\/154405910508400801","article-title":"Epithelial-mesenchymal transformation during craniofacial development.","volume":"84","author":"Kang","year":"2005","journal-title":"J. Dent. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1002\/ajmg.c.31381","article-title":"Genetics of cleft lip and cleft palate.","author":"Leslie","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2020.110382","article-title":"Effects of small interfering RNA-mediated silencing of susceptibility genes of non-syndromic cleft lip with or without cleft palate on cell proliferation and migration.","volume":"138","author":"Li","year":"2020","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"3181","DOI":"10.1158\/0008-5472.Can-14-3721","article-title":"Amplification of long noncoding RNA ZFAS1 promotes metastasis in hepatocellular carcinoma.","volume":"75","author":"Li","year":"2015","journal-title":"Cancer Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ydbio.2011.05.002","article-title":"The inductive role of Wnt-\u03b2-Catenin signaling in the formation of oral apparatus.","volume":"356","author":"Lin","year":"2011","journal-title":"Dev. Biol."},{"key":"B25","first-page":"1450","article-title":"LncRNA ZFAS1 promotes growth and metastasis by regulating BMI1 and ZEB2 in osteosarcoma.","volume":"7","author":"Liu","year":"2017","journal-title":"Am. J. Cancer Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"6472","DOI":"10.1111\/jcmm.15298","article-title":"Hypermethylation-mediated down-regulation of lncRNA TBX5-AS1:2 in Tetralogy of Fallot inhibits cell proliferation by reducing TBX5 expression.","volume":"24","author":"Ma","year":"","journal-title":"J. Cell Mol. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s11684-020-0778-5","article-title":"Long non-coding RNA SAP30-2:1 is downregulated in congenital heart disease and regulates cell proliferation by targeting HAND2.","volume":"15","author":"Ma","year":"","journal-title":"Front. Med."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.635","article-title":"Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and\/or palate.","volume":"7","author":"Mohamad Shah","year":"2019","journal-title":"Mol. Genet. Genomic. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"5661","DOI":"10.1038\/onc.2017.184","article-title":"LncRNA-mediated regulation of cell signaling in cancer.","volume":"36","author":"Peng","year":"2017","journal-title":"Oncogene"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6204","DOI":"10.3390\/ijms13056204","article-title":"Characterization of ARF-BP1\/HUWE1 interactions with CTCF, MYC, ARF and p53 in MYC-driven B cell neoplasms.","volume":"13","author":"Qi","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"8449","DOI":"10.1074\/jbc.M117.814699","article-title":"The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells.","volume":"293","author":"Roy","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2019.11.93","article-title":"Integrated analysis identifying long non-coding RNAs (lncRNAs) for competing endogenous RNAs (ceRNAs) network-regulated palatal shelf fusion in the development of mouse cleft palate.","volume":"7","author":"Shu","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ydbio.2020.02.006","article-title":"The conserved and divergent roles of Prdm3 and Prdm16 in zebrafish and mouse craniofacial development.","volume":"461","author":"Shull","year":"2020","journal-title":"Dev. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3161","DOI":"10.1242\/dev.037440","article-title":"Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion.","volume":"136","author":"Song","year":"2009","journal-title":"Development"},{"key":"B35","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1038\/ng.2971","article-title":"Long-range enhancers regulating Myc expression are required for normal facial morphogenesis.","volume":"46","author":"Uslu","year":"2014","journal-title":"Nat. Genet."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1105-0","article-title":"LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer.","volume":"18","author":"Wang","year":"2019","journal-title":"Mol. Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.143","article-title":"Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer.","volume":"8","author":"Wang","year":"2017","journal-title":"Cell Death Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/eos.12587","article-title":"Interaction between interferon regulatory factor 6 and glycine receptor beta shows a protective effect on developing nonsyndromic cleft lip with or without cleft palate in the Han Chinese population.","volume":"127","author":"Wu","year":"2019","journal-title":"Eur. J. Oral. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4620","DOI":"10.1002\/jcb.27750","article-title":"Identification of differentially expressed long noncoding RNAs in human knee osteoarthritis.","volume":"120","author":"Xiao","year":"2019","journal-title":"J. Cell Biochem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"5648","DOI":"10.1038\/onc.2015.18","article-title":"SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer.","volume":"34","author":"Xu","year":"2015","journal-title":"Oncogene"},{"key":"B41","first-page":"71","article-title":"Role of long noncoding RNA in neuroblastoma.","volume":"30","author":"Ye","year":"","journal-title":"Discov. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"3050","DOI":"10.7150\/ijbs.48126","article-title":"Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition.","volume":"16","author":"Ye","year":"","journal-title":"Int. J. Biol. Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.3892\/or.2019.7257","article-title":"Linc01105 acts as an oncogene in the development of neuroblastoma.","volume":"42","author":"Ye","year":"2019","journal-title":"Oncol. Rep."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1002\/humu.23859","article-title":"Rs2262251 in lncRNA RP11-462G12.2 is associated with nonsyndromic cleft lip with\/without cleft palate.","volume":"40","author":"Yun","year":"2019","journal-title":"Hum. Mutat."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0454-8","article-title":"CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7.","volume":"9","author":"Zeng","year":"2018","journal-title":"Cell Death Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.celrep.2015.08.069","article-title":"LncRNA HOTAIR enhances the androgen-receptor-mediated transcriptional program and drives castration-resistant prostate cancer.","volume":"13","author":"Zhang","year":"2015","journal-title":"Cell Rep."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6254308","article-title":"Targeting YOD1 by RNA interference inhibits proliferation and migration of human oral keratinocytes through transforming growth factor-\u03b23 signaling pathway.","volume":"2018","author":"Zhou","year":"2018","journal-title":"Biomed. Res. Int."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.662780\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T04:23:11Z","timestamp":1624940591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.662780\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,29]]},"references-count":47,"alternative-id":["10.3389\/fcell.2021.662780"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.662780","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,29]]},"article-number":"662780"}}