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Its role during prenatal exposure, however, remains unknown. Here, we use a combination of proteomic, genomic and behavioral approaches to establish ACSS2 as a key mediator of prenatal alcohol exposure-related phenotypes. We define the developmental window during which ACSS2 translocates to nuclei in the mouse brain, and show that alcohol-derived acetate is incorporated into fetal brain histone acetylation in utero. Using genetically engineered mice not expressing ACSS2, we demonstrate that loss of this enzyme attenuates chronic prenatal alcohol exposure-induced craniofacial abnormalities, motor function deficits, cognitive impairments as well as associated chromatin and gene expression changes in the dorsal hippocampus and the cerebellar vermis. Our results outline a previously unknown mechanism underlying prenatal alcohol exposure-related phenotypes regulated by ACSS2, which will inform the development of future therapeutic interventions.<\/jats:p>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>ACSS2 translocates to nuclei during in utero brain development<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Alcohol-derived acetate is incorporated into fetal brain histone acetylation<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Prenatal alcohol exposure results in long-lasting and ACSS2-dependent chromatin and gene expression changes in the hippocampus and cerebellar vermis<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Loss of ACSS2 attenuates molecular changes, craniofacial abnormalities and cognitive impairments linked to prenatal alcohol exposure<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.26.690774","type":"posted-content","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T18:40:12Z","timestamp":1764614412000},"source":"Crossref","is-referenced-by-count":0,"title":["ACSS2 mediates prenatal alcohol exposure-related morphological and behavioral 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