{"id":430,"title":"CircACVR2A(2-4) regulates stem cell pluripotency by uncoupling CDK-activating kinase functions","title_zh":"circACVR2A(2-4)通过解偶联CDK激活激酶功能调控干细胞多能性","url":"https://pubmed.ncbi.nlm.nih.gov/42866953","doi":"10.1093/nar/gkag964","pmid":"42866953","journal":"Nucleic Acids Res","kind":"paper","lang":"en","published_at":"2026-10-13T00:00:00+00:00","fetched_at":"2026-11-08T03:44:13+00:00","authors":["Webb S","Conn VM","van Battum EY","Kirk K","Geiger AB","Singh S","Gabryelska M","Roach MJ","Marri S","Lin H","Liu R","Binelli J","Toubia J","Tran J","Colella AD","Colunga T","Kulik M","Bardy C","Jolly L","Pasterkamp RJ","McKinnon RA","Dalton S","Kristensen LS","Sullivan AE","Conn SJ"],"primary_topic":"early-embryo","topics":[{"slug":"early-embryo","score":5.0,"hits":["lineage specification","pluripotency"]}],"topic_score":5.0,"preference_score":0.0,"preference_labels":[],"llm_score":68.0,"final_score":74.0,"score_dims":{"novelty":85,"rigor":78,"impact":66,"relevance":42,"translation":32},"recommend_reason":"首次揭示circRNA通过解偶联CAK复合物活性调控RNAPII暂停与干细胞命运决定，机制新颖、多模型验证较扎实；但对象为干细胞分化与神经外胚层/胶质瘤，与生殖医学和ART临床的直接关联较弱，属于外围机制参考。","keywords":["circRNA","干细胞多能性","CDK激活激酶(CAK)","RNA聚合酶II暂停","神经外胚层分化","胚层谱系分化"],"selected":1,"story_id":410,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-top-journals","source_name":"PubMed · CNS/大子刊/四大医学刊（生殖相关）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"nar","journal_tier":"general-top","journal_if":16.6,"is_mock":false,"summary_zh":"研究系统性分析了人胚胎干细胞向五个胚层来源谱系分化过程中的circRNA与mRNA表达谱，并对动态变化的circRNA进行靶向沉默。结果显示，敲低circACVR2A(2-4)（而非其线性对应物）可致多能性快速丧失并出现神经外胚层偏向分化。机制上，该circRNA与CAK复合物中的cyclin H结合，在不激活CDK的情况下调节RNAPII磷酸化，与神经外胚层预备位点RNAPII暂停去稳定相一致。小鼠胚胎脑内沉默该circRNA可损害神经元迁移，原位胶质瘤移植模型中则减缓肿瘤进展。","summary":"Differentiation of stem cells is driven by tightly coordinated transcriptional programs, yet the contribution of circular RNAs (circRNAs) to lineage specification remains poorly defined. Here, we profiled circRNA and messenger RNA expression during differentiation of human embryonic stem cells into five germ layer-derived lineages. Targeted silencing of dynamically regulated circRNAs revealed that depletion of circACVR2A(2-4), but not its linear counterpart, induced rapid loss of pluripotency accompanied by neuroectoderm-biased differentiation, phenotypically and transcriptionally. Mechanistically, circACVR2A(2-4) interacts with cyclin H within the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex to modulate RNA polymerase II (RNAPII) phosphorylation independently of CDK activation, with lineage commitment consistent with destabilization of RNAPII pausing at poised neuroectodermal loci. In vivo, circACVR2A(2-4) silencing impaired neuronal migration in the embryonic mouse brain and attenuated glioblastoma progression in mouse orthotopic xenografts. Together, these findings identify a circRNA-mediated mechanism that uncouples CAK complex activity to modulate stem cell fate.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}