ACSS2 mediates prenatal alcohol exposure-related morphological and behavioral phenotypes.

UNLABELLED: The metabolic enzyme Acetyl-CoA Synthetase 2 (ACSS2) recently emerged as an unexpected regulator of molecular and behavioral changes associated with alcohol use. 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.

HIGHLIGHTS: ACSS2 translocates to nuclei during in utero brain developmentAlcohol-derived acetate is incorporated into fetal brain histone acetylationPrenatal alcohol exposure results in long-lasting and ACSS2-dependent chromatin and gene expression changes in the hippocampus and cerebellar vermisLoss of ACSS2 attenuates molecular changes, craniofacial abnormalities and cognitive impairments linked to prenatal alcohol exposure.