Temporal dynamics and mechanisms underlying epigenetic changes in Huntington’s disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.

亨廷顿病（HD）是一种主要影响纹状体的神经退行性疾病，其表观遗传变化的时间动态和机制仍不清楚。使用缓慢进展的敲入小鼠模型，我们描绘了两个早期疾病阶段的 HD 纹状体染色质景观。与细胞类型特异性纹状体增强子和转录组数据库的数据整合表明，在运动缺陷出现之前，从前驱阶段开始，与年龄相关的表观遗传重塑和神经元和胶质细胞特异性基因的转录变化加速。我们还发现，3D 染色质结构虽然通常保留在神经元增强子处，但在疾病位点发生了改变。具体来说，我们发现 HD 突变（ Htt基因中的 CAG 扩展）局部损害了空间染色质组织和近端基因调控。因此，我们的数据为 HD 纹状体中染色质结构变化的两种早期且不同的机制提供了证据，这些变化与转录变化相关：HD 突变全局加速了脑细胞身份的年龄依赖性表观遗传和转录重编程，并局部影响 3D 染色质组织。