Integrative multi-omics landscape of fluoxetine action across 27 brain regions

We constructed a comprehensive multi-omics map of the molecular effects of fluoxetine (an SSRI antidepressant), in 27 rat brain regions. We profiled gene expression (bulk RNA-seq, 210 datasets) and chromatin state (bulk chromatin immunoprecipitation sequencing (ChIP-seq) for the histone marker H3K27ac, 100 datasets) in a broad, unbiased panel of 27 brain regions across the entire rodent brain, in naive and fluoxetine-treated animals. We complemented this approach with single-cell RNA-seq (scRNA-seq) analysis of two brain regions. Using diverse integrative data analysis techniques we characterized the complex and multifaceted effects of fluoxetine on region-specific and cell-type-specific gene regulatory networks and pathways. Remarkably, we observed profound molecular changes across the brain (>4,000 differentially expressed genes and differentially acetylated ChIP-seq peaks each) that were highly region-dependent. We leveraged this atlas to identify fluoxetine-moduated genes and gene-regulatory loci, predict enriched motifs that suggest potential upstream regulators, and validate global mechanisms of fluoxetine action.本研究构建了氟西汀（fluoxetine，一种选择性5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药）在27个大鼠脑区中产生分子效应的综合多组学图谱。本研究针对覆盖全啮齿类脑部的27个脑区组成的宽泛无偏检测队列，在未给药（空白对照）及氟西汀处理的动物中，对基因表达（批量RNA测序（bulk RNA-seq），共210套数据集）与染色质状态（针对组蛋白标记物H3K27ac的批量染色质免疫沉淀测序（ChIP-seq），共100套数据集）进行了谱学分析。本研究还辅以两个脑区的单细胞RNA测序（scRNA-seq）分析，以完善上述研究体系。借助多样化的整合数据分析技术，本研究阐明了氟西汀对脑区特异性及细胞类型特异性基因调控网络与通路的复杂多面效应。值得注意的是，我们在全脑范围内观测到了显著的分子变化（分别包含超过4000个差异表达基因与差异乙酰化ChIP-seq峰），且此类变化具有极强的脑区依赖性。本研究依托该多组学图谱，成功鉴定出氟西汀调控的基因及基因调控位点，预测出可提示潜在上游调控因子的富集基序，并验证了氟西汀发挥作用的全局分子机制。