{"id":527,"title":"Genetic dissection of cell type–specific congenital heart disease variants reveals ETS1 control of vascular smooth muscle cell fate","title_zh":"先天性心脏病细胞类型特异性变异的遗传解析揭示ETS1调控血管平滑肌细胞命运","url":"https://doi.org/10.1126/sciadv.aeg4687","doi":"10.1126/sciadv.aeg4687","pmid":null,"journal":"Science Advances","kind":"paper","lang":"en","published_at":"2026-11-06T00:00:00+00:00","fetched_at":"2026-11-08T03:45:22+00:00","authors":["Xin Li","Mingzhu Fu","Shengtao Jia","Zhenwei Wu","Long Pang","Ke Xiong","Yujun Wang","Wen Li","Aibin He","Shanshan Ai"],"primary_topic":"ethics-policy","topics":[{"slug":"ethics-policy","score":3.0,"hits":["crispr","regulation","regulatory"]},{"slug":"omics-methods","score":1.0,"hits":["single-cell"]}],"topic_score":3.0,"preference_score":0.0,"preference_labels":[],"llm_score":70.0,"final_score":78.0,"score_dims":{"novelty":88,"rigor":88,"impact":62,"relevance":38,"translation":40},"recommend_reason":"方法学新颖，单细胞多组学解析非编码变异与染色质状态的关系，对胚胎发育与调控变异研究有参考价值；但研究对象为先心病而非生殖/ART核心问题，临床转化相关性有限。","keywords":["先天性心脏病","单细胞多组学","非编码变异","ETS1","血管平滑肌细胞","染色质状态"],"selected":1,"story_id":9,"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":"sci-adv","journal_tier":"cns-sub","journal_if":11.7,"is_mock":false,"summary_zh":"该研究在人心脏分化过程中联合检测单细胞H3K27ac、H3K27me3、H3K4me3和转录组，构建单细胞多组学图谱并将顺式调控元件分为六种染色质状态，优先筛选出610个富集于谱系和状态特异性调控区的先心病非编码变异。CRISPR敲入验证这些变异可扰动邻近基因表达并损害心脏分化。进一步解析ETS1附近Polycomb标记变异，发现局部H3K27me3丢失、H3K27ac增加和ETS1上调，使分化转向第二心场祖细胞及高迁移性ETS1+血管平滑肌细胞，揭示非编码变异通过ETS1驱动异常血管平滑肌命运承诺。","summary":"Numerous congenital heart disease (CHD) risk variants lie in cis-regulatory elements, yet the impact of variants in repressed and bivalent chromatin on cell type–specific heart development is unclear. Here, we generated a single-cell multiomic atlas of human cardiac differentiation by jointly profiling H3K27ac, H3K27me3, H3K4me3, and transcriptomes in individual cells, classifying cis-regulatory elements into six chromatin states, enabling prioritization of 610 CHD-associated noncoding variants enriched in lineage- and state-specific regulatory elements, including repressive and bivalent regions. CRISPR knockin of selected variants perturbed nearby gene expression and impaired cardiac differentiation. Dissection of a Polycomb-marked variant near ETS1 (ETS proto-oncogene 1) revealed local H3K27me3 loss, H3K27ac gain, and ETS1 up-regulation, which redirects differentiation toward second-heart-field progenitors with epithelial characteristics at early stages and, ultimately, highly migratory ETS1 + vascular smooth muscle cells. Together, our work establishes a single-cell chromatin-state framework for interpreting noncoding CHD risk variants and uncovers an ETS1-driven program linking Polycomb-deregulated noncoding variation to aberrant vascular smooth muscle fate commitment during human cardiogenesis.","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}}