Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA; Center for Research Computing, University of Pittsburgh, Pittsburgh, PA, USA.
Mol Cell Endocrinol. 2023 Mar 1;563:111864. doi: 10.1016/j.mce.2023.111864. Epub 2023 Jan 20.
Prenatal exposure to synthetic glucocorticoids (sGCs) reprograms brain development and predisposes the developing fetus towards potential adverse neurodevelopmental outcomes. Using a mouse model of sGC administration, previous studies show that these changes are accompanied by sexually dimorphic alterations in the transcriptome of neural stem and progenitor cells (NSPCs) derived from the embryonic telencephalon. Because cell type-specific gene expression profiles tightly regulate cell fate decisions and are controlled by a flexible landscape of chromatin domains upon which transcription factors and enhancer elements act, we multiplexed data from four genome-wide assays: RNA-seq, ATAC-seq (assay for transposase accessible chromatin followed by genome wide sequencing), dual cross-linking ChIP-seq (chromatin immunoprecipitation followed by genome wide sequencing), and microarray gene expression to identify novel relationships between gene regulation, chromatin structure, and genomic glucocorticoid receptor (GR) action in NSPCs. These data reveal that GR binds preferentially to predetermined regions of accessible chromatin to influence gene programming and cell fate decisions. In addition, we identify SOX2 as a transcription factor that impacts the genomic response of select GR target genes to sGCs (i.e., dexamethasone) in NSPCs.
产前暴露于合成糖皮质激素（sGC）会重新编程大脑发育，并使发育中的胎儿易发生潜在的不良神经发育结局。使用 sGC 给药的小鼠模型，先前的研究表明，这些变化伴随着来自胚胎端脑的神经干细胞和祖细胞（NSPC）转录组的性别二态性改变。由于细胞类型特异性基因表达谱紧密调节细胞命运决定，并且受到转录因子和增强子元件作用的灵活染色质域景观控制，我们对来自四个全基因组检测的数据进行了多重分析：RNA-seq、ATAC-seq（转座酶可及染色质的测定，随后进行全基因组测序）、双交联 ChIP-seq（染色质免疫沉淀，随后进行全基因组测序）和微阵列基因表达，以鉴定 NSPC 中基因调控、染色质结构和基因组糖皮质激素受体（GR）作用之间的新关系。这些数据表明，GR 优先结合预先确定的可及染色质区域，以影响基因编程和细胞命运决定。此外，我们还确定了 SOX2 作为一种转录因子，它影响了 NSPC 中特定 GR 靶基因对 sGC（即地塞米松）的基因组反应。
