Rescue of Down syndrome related deficits by Brwd1 copy number restoration in Ts65Dn mice

With an astounding incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in Down syndrome neurons and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. In order to confirm relevance of Ts65Dn to human DS etiology, we first performed bulk RNA-seq profiling on E17.5 Ts65Dn vs. euploid forebrain tissues. Furthermore, in order to further evaluate the effects of Brwd1 rescue within the context of adult brain, we performed bulk RNA-seq on hippocampal tissues from 6-week-old male and female animals, comparing Ts65Dn vs. euploid and Ts65Dn;Brwd1+/- genotypes .唐氏综合征（Down syndrome, DS）是全球范围内最常见的与智力障碍相关的染色体疾病，其发病率惊人，约为每800例活产中出现1例。尽管已明确唐氏综合征的遗传学基础为21号染色体（HSA21）三体，但由HSA21编码的、直接导致认知缺陷的基因仍未完全阐明。本研究发现，由HSA21编码的染色质效应因子BRWD1在唐氏综合征神经元以及三体模型小鼠的脑组织中表达上调。我们证实，在三体动物中选择性恢复Brwd1的拷贝数，可挽救海马长时程增强（long-term potentiation, LTP）、认知功能以及基因表达的缺陷。我们证明，Brwd1可与BAF染色质重塑复合物紧密结合，而Brwd1表达升高会促进BAF复合物在基因组中的错误靶向。尤为重要的是，恢复Brwd1的正常表达可纠正异常的BAF定位，同时改善染色质开放性与基因表达的相关改变。这些发现确立了BRWD1作为正常神经发育的关键表观基因组介导因子，以及唐氏综合征相关表型的重要致病因素的地位。为验证Ts65Dn模型与人类唐氏综合征致病机制的相关性，我们首先对胎龄E17.5的Ts65Dn与整倍体前脑组织进行了批量RNA测序（bulk RNA-seq）分析。此外，为进一步评估成年脑内Brwd1挽救策略的效果，我们对6周龄雌雄小鼠的海马组织开展了批量RNA测序，比较了Ts65Dn、整倍体与Ts65Dn;Brwd1+/-三种基因型的组织转录组差异。