Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Pathology, Stanford Medical School, Palo Alto, CA, 94305, USA.
Nat Commun. 2022 Oct 26;13(1):6384. doi: 10.1038/s41467-022-34200-0.
With an 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 neurons derived from iPS cells from an individual with Down syndrome 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.
唐氏综合征（DS）的发病率约为每 800 例出生婴儿中有 1 例，是全球与智力障碍相关的最常见的染色体疾病。虽然 DS 的遗传基础已被确定为 21 号染色体（HSA21）的三倍体，但直接导致认知缺陷的 HSA21 编码基因仍不完全清楚。在这里，我们发现唐氏综合征个体诱导多能干细胞衍生的神经元和三体小鼠的大脑中，HSA21 编码的染色质效应因子 BRWD1 上调。我们表明，在三体动物中选择性地增加 Brwd1 的拷贝数可恢复海马体 LTP、认知和基因表达的缺陷。我们证明 Brwd1 与 BAF 染色质重塑复合物紧密结合，并且表达增加会促进 BAF 基因组的错误靶向。重要的是，Brwd1 的正常化可纠正异常的 BAF 定位，以及与染色质可及性和基因表达相关的变化。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体，以及 DS 相关表型的重要贡献者。
