{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T10:01:29Z","timestamp":1790330489527,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"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>Polyadenylation, a core transcriptional step governed by polyadenylation signals (PAS), functionally interacts with transcription. Nevertheless, how PAS sequences respond to variable transcriptional output remains poorly characterized. Here, we precisely modulated cellular transcription levels by integrating SV40 promoter truncation with a Tet-On dual-luciferase reporter system. Diminished polyadenylation efficiency accompanies lowered promoter activity, and graded transcription assays revealed a tiered PAS processing model: canonical and suboptimal PASs maintain stable 3\u2032-end processing at high transcription levels, whereas non-canonical PASs display compromised processing efficiency with rising transcription. During forskolin(FSK)-induced BeWo cell syncytialization, endogenous trophoblast fusion genes carrying potent canonical PASs were selectively mobilized upon transcriptional activation to enrich differentiation transcripts and sustain orderly syncytiotrophoblast maturation. Together, these findings reveal a hierarchical transcription-polyadenylation axis that associate with placental trophoblast syncytialization. They fill key gaps in mRNA processing and provide a foundation for studying the transcriptional regulatory mechanisms underlying trophoblast differentiation.<\/jats:p>","DOI":"10.3389\/fcell.2026.1958080","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:16:02Z","timestamp":1790327762000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcription-dependent polyadenylation signal activity contributes to transcriptomic regulation during Forskolin-induced BeWo cell syncytialization"],"prefix":"10.3389","volume":"14","author":[{"given":"Juan","family":"Liu","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guolin","family":"Ye","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control","place":["Beijing, China"]},{"name":"School of Public Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Agriculture and Biomanufacturing, Zhengzhou University","place":["Zhengzhou, China"]},{"name":"Biology and Agriculture Research Center, University of Science and Technology Beijing","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Jing","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control","place":["Beijing, China"]},{"name":"School of Public Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control","place":["Beijing, China"]},{"name":"School of Public Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyuan","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Agriculture and Biomanufacturing, Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyu","family":"Ning","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control","place":["Beijing, China"]},{"name":"School of Public Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.1261\/rna.2162610","article-title":"RiboSys, a high-resolution, quantitative approach to measure the in vivo kinetics of pre-mRNA splicing and 3'-end processing in Saccharomyces cerevisiae","volume":"16","author":"Alexander","year":"2010","journal-title":"RNA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2969","DOI":"10.1101\/gad.1362305","article-title":"A role for the CPF 3'-end processing machinery in RNAP II-dependent gene looping","volume":"19","author":"Ansari","year":"2005","journal-title":"Genes Dev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1101\/gr.10.7.1001","article-title":"Patterns of variant polyadenylation signal usage in human genes","volume":"10","author":"Beaudoing","year":"2000","journal-title":"Genome Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1261\/rna.556107","article-title":"Poly(A)-binding protein is differentially required for translation mediated by viral internal ribosome entry sites","volume":"13","author":"Bradrick","year":"2007","journal-title":"RNA"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1101\/gad.250993.114","article-title":"CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3' processing","volume":"28","author":"Chan","year":"2014","journal-title":"Genes Dev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3182","DOI":"10.1038\/s41467-020-16959-2","article-title":"Widespread transcript shortening through alternative polyadenylation in secretory cell differentiation","volume":"11","author":"Cheng","year":"2020","journal-title":"Nat. Commun."},{"key":"B7","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.rbmo.2015.10.005","article-title":"The endocrine function of human placenta: an overview","volume":"32","author":"Costa","year":"2016","journal-title":"Reprod. Biomed. Online"},{"key":"B8","doi-asserted-by":"publisher","first-page":"279","DOI":"10.3390\/ijms19010279","article-title":"Useful bicistronic reporter System for studying Poly(A) site-defining cis elements and regulation of alternative polyadenylation","volume":"19","author":"Deng","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.molcel.2011.08.017","article-title":"Mechanisms and consequences of alternative polyadenylation","volume":"43","author":"Di Giammartino","year":"2011","journal-title":"Mol. Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.1093\/emboj\/cdf390","article-title":"Yhh1p\/Cft1p directly links poly(A) site recognition and RNA polymerase II transcription termination","volume":"21","author":"Dichtl","year":"2002","journal-title":"EMBO J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4771","DOI":"10.1093\/emboj\/17.16.4771","article-title":"Poly(A) signals control both transcriptional termination and initiation between the tandem GAL10 and GAL7 genes of Saccharomyces cerevisiae","volume":"17","author":"Greger","year":"1998","journal-title":"EMBO J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1111\/j.1399-0039.2004.00140.x","article-title":"HLA DQA1 genes generate multiple transcripts by alternative splicing and polyadenylation of the 3' untranslated region","volume":"63","author":"Hoarau","year":"2004","journal-title":"Tissue Antigens"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1039\/c003229h","article-title":"Using the Tet-On system to develop a procedure for extracting transcription factor activation dynamics","volume":"6","author":"Huang","year":"2010","journal-title":"Mol. Biosyst."},{"key":"B14","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1042\/BJ20071255","article-title":"Cathepsin L expression is up-regulated by hypoxia in human melanoma cells: role of its 5'-untranslated region","volume":"413","author":"Jean","year":"2008","journal-title":"Biochem. J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"7028","DOI":"10.1073\/pnas.0900028106","article-title":"Progressive lengthening of 3' untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development","volume":"106","author":"Ji","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B16","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1038\/msb.2011.69","article-title":"Transcriptional activity regulates alternative cleavage and polyadenylation","volume":"7","author":"Ji","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"6603","DOI":"10.1093\/emboj\/cdf633","article-title":"Control of poly(A) polymerase level is essential to cytoplasmic polyadenylation and early development in Drosophila","volume":"21","author":"Juge","year":"2002","journal-title":"EMBO J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1261\/rna.1622010","article-title":"Poly(A) signal-dependent degradation of unprocessed nascent transcripts accompanies poly(A) signal-dependent transcriptional pausing in vitro","volume":"16","author":"Kazerouninia","year":"2010","journal-title":"RNA"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2604","DOI":"10.1101\/gad.1823609","article-title":"A physiological role for gene loops in yeast","volume":"23","author":"Lain\u00e9","year":"2009","journal-title":"Genes Dev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"8960","DOI":"10.1074\/jbc.M115.687491","article-title":"Promoter-Terminator gene loops affect alternative 3'-End processing in yeast","volume":"291","author":"Lamas-Maceiras","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s00294-016-0645-8","article-title":"Polyadenylation site selection: linking transcription and RNA processing via a conserved carboxy-terminal domain (CTD)-interacting protein","volume":"63","author":"Larochelle","year":"2017","journal-title":"Curr. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2594","DOI":"10.1080\/15476286.2021.1933732","article-title":"Alternative polyadenylated mRNAs behave as asynchronous rhythmic transcription in Arabidopsis","volume":"18","author":"Lin","year":"2021","journal-title":"RNA Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s13619-025-00250-0","article-title":"Poly(A) tail regulation in stem cells and early development","volume":"14","author":"Miao","year":"2025","journal-title":"Cell Regen."},{"key":"B24","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1038\/s41580-022-00507-5","article-title":"Context-specific regulation and function of mRNA alternative polyadenylation","volume":"23","author":"Mitschka","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1261\/rna.103206","article-title":"The conserved AAUAAA hexamer of the poly(A) signal can act alone to trigger a stable decrease in RNA polymerase II transcription velocity","volume":"12","author":"Nag","year":"2006","journal-title":"RNA"},{"key":"B26","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.molcel.2011.01.022","article-title":"Transcriptional activators enhance polyadenylation of mRNA precursors","volume":"41","author":"Nagaike","year":"2011","journal-title":"Mol. Cell."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1038\/ng1411","article-title":"Gene loops juxtapose promoters and terminators in yeast","volume":"36","author":"O'Sullivan","year":"2004","journal-title":"Nat. Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4092","DOI":"10.1128\/mcb.24.10.4092-4103.2004","article-title":"The two steps of poly(A)-dependent termination, pausing and release, can be uncoupled by truncation of the RNA polymerase II carboxyl-terminal repeat domain","volume":"24","author":"Park","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1126\/science.159.3822.1467","article-title":"Human hormone production in vitro","volume":"159","author":"Pattillo","year":"1968","journal-title":"Science"},{"key":"B30","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/s0092-8674(02)00617-7","article-title":"Integrating mRNA processing with transcription","volume":"108","author":"Proudfoot","year":"2002","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3389\/fendo.2013.00053","article-title":"Alterations in polyadenylation and its implications for endocrine disease","volume":"4","author":"Rehfeld","year":"2013","journal-title":"Front. Endocrinol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1910","DOI":"10.1261\/rna.033019.112","article-title":"IRES-dependent translation of egr2 is induced under inflammatory conditions","volume":"18","author":"R\u00fcbsamen","year":"2012","journal-title":"RNA"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1126\/science.1155390","article-title":"Proliferating cells express mRNAs with shortened 3' untranslated regions and fewer microRNA target sites","volume":"320","author":"Sandberg","year":"2008","journal-title":"Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1101\/gad.250985.114","article-title":"Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33","volume":"28","author":"Sch\u00f6nemann","year":"2014","journal-title":"Genes Dev."},{"key":"B35","doi-asserted-by":"publisher","first-page":"E1419","DOI":"10.1073\/pnas.1718723115","article-title":"Molecular basis for the recognition of the human AAUAAA polyadenylation signal","volume":"115","author":"Sun","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B36","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1126\/science.1224350","article-title":"Gene loops enhance transcriptional directionality","volume":"338","author":"Tan-Wong","year":"2012","journal-title":"Science"},{"key":"B37","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/21541264.2022.2114776","article-title":"Alternative polyadenylation regulation: insights from sequential polyadenylation","volume":"13","author":"Tang","year":"2022","journal-title":"Transcription"},{"key":"B38","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/nrm.2016.116","article-title":"Alternative polyadenylation of mRNA precursors","volume":"18","author":"Tian","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1101\/gr.237826.118","article-title":"A compendium of conserved cleavage and polyadenylation events in mammalian genes","volume":"28","author":"Wang","year":"2018","journal-title":"Genome Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/s0168-3659(02)00059-7","article-title":"Strength evaluation of transcriptional regulatory elements for transgene expression by adenovirus vector","volume":"81","author":"Xu","year":"2002","journal-title":"J. Control. Release."},{"key":"B41","doi-asserted-by":"publisher","first-page":"18773","DOI":"10.1073\/pnas.1211101109","article-title":"Transcriptome-wide analyses of CstF64-RNA interactions in global regulation of mRNA alternative polyadenylation","volume":"109","author":"Yao","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2268","DOI":"10.1038\/s41467-018-04730-7","article-title":"Cellular stress alters 3'UTR landscape through alternative polyadenylation and isoform-specific degradation","volume":"9","author":"Zheng","year":"2018","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1958080\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:16:04Z","timestamp":1790327764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1958080\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":42,"alternative-id":["10.3389\/fcell.2026.1958080"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1958080","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"article-number":"1958080"}}