HDAC inhibitor treatment restores transcriptome, chromatin accessibility, and memory deficits in a mouse model for Down syndrome.

IF 4.5 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2026-09-30 eCollection Date: 2026-10-16 DOI:10.1016/j.isci.2026.117670

Cesar Sierra, René A J Crans, Mara Dierssen

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引用次数: 0

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.

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HDAC抑制剂治疗可恢复唐氏综合症小鼠模型的转录组、染色质可及性和记忆缺陷。

唐氏综合症（DS）与广泛的分子改变有关，包括基因表达异常，不仅影响21号染色体基因，而且扰乱整个转录组。这种改变的全基因组性质表明它可能是表观遗传介导的，鉴于表观遗传修饰的可逆性，这也可能提供治疗机会。本研究表明，三体小鼠模型Ts65Dn海马整体乙酰化水平的降低与海马神经元基因启动子染色质可及性的降低有关。引人注目的是，使用临床批准的组蛋白去乙酰化酶抑制剂亚eroylanilide羟肟酸（SAHA）对三体小鼠的组蛋白乙酰化进行药理学恢复，使转录组、表观遗传和皮质海马记忆缺陷正常化。这种拯救是由意外的多生染色体异色化介导的。总之，我们的研究结果确定了一种意想不到的表观遗传机制，将组蛋白乙酰化动力学与染色体剂量稳态联系起来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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