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Using high-resolution epigenetic profiling of postmortem human cell types we identify a pathogenic cascade linking cell type specific enhancer activity to somatic CAG expansion, and toxicity to epigenetic dysregulation. Enhancers regulating mismatch-repair (MMR) gene expression explain the specificity of expansion. In the second, toxic phase of HD we identify two distinct epigenetic mechanisms that disrupt regulation of hundreds of genes in the majority of HD MSNs, including several that cause haploinsufficient neurological disorders. Together, these data unify enhancer function, impaired DNA demethylation, and transcriptional dysregulation into a single model highlighting therapeutic opportunities that combine inhibition of somatic CAG expansion with restoration of neuronal DNA demethylation.<\/jats:p>","DOI":"10.1101\/2025.05.21.653721","type":"posted-content","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T18:15:13Z","timestamp":1748283313000},"source":"Crossref","is-referenced-by-count":9,"title":["Epigenetic mechanisms governing cell type specific somatic expansion and toxicity in Huntington\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6518-3296","authenticated-orcid":false,"given":"Matthew","family":"Baffuto","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, The Rockefeller University, New York, NY, United States of 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