{"id":506,"title":"Wt1 splice isoforms bias lineage programmes during formative pluripotency","title_zh":"Wt1 剪接异构体在形成性多能性阶段偏向调控谱系转录程序","url":"https://doi.org/10.1038/s41467-026-79258-2","doi":"10.1038/s41467-026-79258-2","pmid":null,"journal":"Nature Communications","kind":"paper","lang":"en","published_at":"2026-11-04T00:00:00+00:00","fetched_at":"2026-11-08T03:45:21+00:00","authors":["Luis Miguel Cerron-Alvan","Tatiana Firfa","Mattia Pitasi","Anne Löbker","Michelle Huth","Michael Bindl","Leonie Drakos","Triin Laos","Martin Leeb"],"primary_topic":"early-embryo","topics":[{"slug":"early-embryo","score":6.0,"hits":["epiblast","gastrulation","pluripotency"]},{"slug":"ethics-policy","score":1.0,"hits":["regulatory"]},{"slug":"industry","score":1.0,"hits":["acquisition"]}],"topic_score":6.0,"preference_score":0.0,"preference_labels":[],"llm_score":81.0,"final_score":89.0,"score_dims":{"novelty":88,"rigor":85,"impact":72,"relevance":62,"translation":50},"recommend_reason":"首次将可变剪接（WT1 KTS 异构体）确立为原肠胚形成前谱系转录偏向的调控机制，并有 CRISPRa 筛选、体内外验证及人源细胞保守性支持；对早期胚胎发育与多能性研究有较高参考价值，但与临床 ART 的直接转化尚远。","keywords":["Wt1","可变剪接","形成性多能性","谱系偏向","上胚层","CRISPRa 筛选"],"selected":1,"story_id":69,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"crossref-cns","source_name":"Crossref · CNS 与大子刊新上线（领域过滤）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"nat-commun","journal_tier":"cns-sub","journal_if":14.7,"is_mock":false,"summary_zh":"该研究利用靶向 CRISPRa 筛选，发现 Wt1 是形成性多能性（formative pluripotency）阶段谱系相关转录程序的调控因子。Wt1 在体外与体内形成性多能性阶段短暂诱导，与谱系偏向的出现同步；提前诱导 Wt1 会推动细胞向着床后身份转变，而 Wt1 缺失细胞虽能退出 naïve 状态，但获得形成性及谱系相关程序受损。WT1 与 OTX2、OCT4、FOXO1 共同结合活跃调控元件。比较剪接异构体显示，KTS 剪接状态是决定前/神经外胚层与后/中胚层转录程序分化的主要因素；E5.5 上胚层中 Wt1 表达与剪接组成与谱系偏向状态一致，且该异构体依赖程序在人类多能细胞中保守。","summary":"Abstract How transcriptional asymmetry arises in the epiblast before gastrulation remains a central question in mammalian development. Using a targeted CRISPRa screen, we identify Wt1 as a regulator of lineage-associated transcriptional programmes during formative pluripotency. Wt1 is transiently induced during formative pluripotency in vitro and in vivo, coincident with emerging lineage biases. Precocious Wt1 induction advances cells toward post-implantation identity, whereas Wt1 -deficient cells execute naïve exit but show impaired acquisition of formative and lineage-associated programmes. WT1 binds active regulatory elements together with OTX2, OCT4 and FOXO1. Comparison of Wt1 splice isoforms identifies KTS splice status as the major determinant of divergent anterior/neuroectodermal and posterior/mesodermal transcriptional programmes in vitro. In the E5.5 epiblast, Wt1 expression and splice composition align with lineage-biased states, linking isoform usage to anterior bias in vivo. Isoform-dependent programmes are conserved in human pluripotent cells. These findings identify alternative splicing as a mechanism tuning lineage-associated transcriptional bias before gastrulation.","interpretation_basis":null,"fulltext_status":"not_found","interpretation":null,"fulltext":{"available":false,"status":"not_found","reason":"Europe PMC 无此记录：DOI 10.1038/s41467-026-79258-2","pmcid":null,"license":null,"chars":0,"source":"Europe PMC","fetched_at":"2026-11-08T04:16:32+00:00"}}