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Using ultra-low-input multi-omics, we profiled H3K27ac, chromatin accessibility, and the transcriptome in both the TE and ICM. Lineage-specific H3K27ac was predominantly enriched at distal enhancers rather than promoters, indicating that first-lineage differentiation relies on distal enhancer activity. Integration with chromatin accessibility data identified key transcription factors cooperating with H3K27ac during peri-implantation. Analysis of high-order chromatin structure revealed lineage-specific enhancer\u2013promoter loops. Further, we identified and functionally validated BRD4, p300, and YY1 at these enhancers, demonstrating their essential roles in morula-to-blastocyst transition. Notably, CBP\/p300 inhibition selectively disrupted distal H3K27ac-marked enhancers with minimal effects on promoters, leading to down-regulation of placenta-related genes. Despite similar accessibility and transcription factor binding between the TE and ICM, enhancer activity requires H3K27ac acquisition rather than accessibility alone. These results indicate that H3K27ac-marked distal enhancers regulate early lineage differentiation by promoting lineage-specific gene expression through long-range chromatin interactions. Cross-species comparisons between mice and humans further revealed stronger H3K27ac conservation in the TE than in the ICM of mammalian embryos, highlighting the conserved regulatory role of TE-specific enhancers during early development.<\/jats:p>","DOI":"10.1093\/nar\/gkag026","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T12:49:48Z","timestamp":1767962988000},"source":"Crossref","is-referenced-by-count":3,"title":["Distal enhancers regulate mammalian early embryonic lineage differentiation through long-range interactions"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9194-9550","authenticated-orcid":false,"given":"Qianshu","family":"Zhu","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Women and Children\u2019s Hospital of Chongqing Medical University , Chongqing 400013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimeng","family":"Guo","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Women and Children\u2019s Hospital of Chongqing Medical University , Chongqing 400013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Xie","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Women and Children\u2019s Hospital of Chongqing Medical University , Chongqing 400013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiadan","family":"Qu","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of 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and Children\u2019s Hospital of Chongqing Medical University , Chongqing 400013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Women and Children\u2019s Hospital of Chongqing Medical University , Chongqing 400013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Dong","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Women and Children\u2019s Hospital of Chongqing Medical University , Chongqing 400013 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