全基因组去卷积揭示了阿尔茨海默病的弹性表观遗传特征。
Whole genome deconvolution unveils Alzheimer's resilient epigenetic signature.
机构信息
Department of Pathology, Stanford University, Stanford, CA, USA.
Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA.
出版信息
Nat Commun. 2023 Aug 16;14(1):4947. doi: 10.1038/s41467-023-40611-4.
Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) accurately depicts the chromatin regulatory state and altered mechanisms guiding gene expression in disease. However, bulk sequencing entangles information from different cell types and obscures cellular heterogeneity. To address this, we developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression across the whole genome. Cellformer enables cost-effective cell type-specific open chromatin profiling in large cohorts. Applied to 191 bulk samples from 3 brain regions, Cellformer identifies cell type-specific gene regulatory mechanisms involved in resilience to Alzheimer's disease, an uncommon group of cognitively healthy individuals that harbor a high pathological load of Alzheimer's disease. Cell type-resolved chromatin profiling unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience that may illuminate therapeutic opportunities to limit the cognitive impact of the disease. Cellformer is freely available to facilitate future investigations using high-throughput bulk ATAC-seq data.
转座酶可及染色质测序（ATAC-seq）分析能够准确描绘染色质调控状态，并揭示疾病中指导基因表达的改变机制。然而，批量测序会混淆来自不同细胞类型的信息，并掩盖细胞异质性。为了解决这个问题，我们开发了 Cellformer，这是一种深度学习方法，可将批量 ATAC-seq 分解为整个基因组中特定细胞类型的表达。Cellformer 能够在大样本量中进行经济高效的特定细胞类型的开放染色质分析。在来自 3 个大脑区域的 191 个批量样本中的应用中，Cellformer 确定了与阿尔茨海默病（一种认知健康但携带高阿尔茨海默病病理负荷的罕见人群）的恢复力相关的特定细胞类型的基因调控机制。细胞类型分辨的染色质分析揭示了特定细胞类型的途径，并提名了潜在的与恢复力相关的表观遗传介质，这可能为限制疾病的认知影响提供治疗机会。Cellformer 可免费使用，以促进使用高通量批量 ATAC-seq 数据进行未来的研究。
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