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To define the epigenetic buffering axis that sustains promoter output during HDAC inhibition in gastric cancer. We integrated pharmacologic profiling across a molecularly diverse gastric cancer panel with an epigenetic\u2010focused pooled CRISPR\u2010Cas9 screening library, domain\u2010resolved genetic perturbation, structure\u2010guided WIN\u2010pocket targeting, CCK8 time\u2010course proliferation assays, and pulse\u2010washout clonogenic recovery assays. Chromatin and transcriptional consequences were interrogated by assessing COMPASS integrity and chromatin association, promoter\u2010proximal H3K4me3 dynamics, data\u2010derived ATAC\u2010seq accessibility, and transcriptional output. WDR5 abundance and baseline H3K4me3 levels were associated with sensitivity to combined HDAC and WDR5 WIN\u2010pocket inhibition. Multiple orthogonal approaches identified the WDR5 WIN pocket as a key interface supporting chromatin\u2010associated COMPASS and promoter\u2010proximal H3K4me3 under the tested conditions. WIN\u2010pocket disruption reduced chromatin recovery of COMPASS\u2010associated components and attenuated H3K4me3 at selected growth\u2010linked promoters. This produced a state with elevated H3K27 acetylation, attenuated H3K4me3, and reduced transcriptional output; data\u2010derived ATAC\u2010enriched regions retained a centered accessibility signal, although the mean peak amplitude was lowest in the combination. HDAC inhibitor response is conditioned by promoter licensing via the WDR5\u2010COMPASS H3K4 methylation axis.<\/jats:p>","DOI":"10.1002\/advs.78255","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:42:11Z","timestamp":1792122131000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disabling COMPASS Promoter Licensing Shifts HDAC\u2010Inhibited Gastric Cancer Toward Sustained Transcriptional Suppression During Recovery"],"prefix":"10.1002","author":[{"given":"Jintian","family":"Song","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Oncology Clinical Oncology School of Fujian Medical University Fujian Cancer Hospital Fujian Branch of Fudan University Shanghai Cancer Center  Fuzhou Fujian People's Republic of 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