HDAC inhibitor treatment restores transcriptome, chromatin accessibility, and memory deficits in a mouse model for Down syndrome
Year: 2026
Type: article
Abstract: Down syndrome (DS) is associated with widespread molecular alterations, including aberrant gene expression, which not only affects chromosome 21 genes but perturbs the whole transcriptome. The genome-wide nature of this alteration suggests that it might be epigenetically mediated, which may also offer therapeutic opportunities given the reversibility of epigenetic modifications. Here, we show that decreased global acetylation level in the hippocampus of the trisomic mouse model Ts65Dn is associated with decreased chromatin accessibility at gene promoters in hippocampal neurons. Strikingly, pharmacological restoration of histone acetylation using the clinically approved histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) normalized transcriptomic, epigenetic, and cortico-hippocampal memory deficits in trisomic mice. This rescue was mediated by an unexpected heterochromatization of the supernumerary chromosome. Altogether, our results identify an unanticipated epigenetic mechanism linking histone acetylation dynamics to chromosomal dosage homeostasis.
Source: iScience
Authors: Cesar Sierra, René A.J. Crans, Mara Dierssen
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,240
Funders: Fundació la Marató de TV3, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, European Commission, Fondation Jérôme Lejeune, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Agencia Estatal de Investigación, H2020 Societal Challenges, NextGenerationEU
Awards: G121809054, G1709043353, G1716201097, G1799927510, G1855990336, G2064873908, G2309174360, G2356618895, G2462415295, G2585926585, G2660406951, Acciones Individuales MSCA - Sello de Excelencia ISCIII-HEALTH, G279363373, G3005324705, G3163305423, G318412399, G3392608217, G3518538256, G3546882995, G430777504, Gene overdosage and comorbidities during the early lifetime in Down Syndrome, G4993905653, G5195188938, G5421974903, G589576360, G647145013, G6520718613, G6656126374, G69051668, G7391727506, G7520681623, G8637226926, G8909725079, G8920660035, G897484643, G9000845090, G9000845213, G9000846659, G99296377
OpenAlex ID: W7214980735