Divergent transcriptional regulation of astrocyte reactivity across disorders.
Divergent transcriptional regulation of astrocyte reactivity across disorders.
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DOI：
10.1038/s41586-022-04739-5
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发表时间：
2022-06
期刊：
影响因子：
64.8
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中科院分区：
文献类型：
--
作者：
星形胶质细胞对所有中枢神经系统（CNS）损伤的反应性变化会影响疾病的结局。这些变化包括差异表达基因（DEG），其背景多样性和调控知之甚少。在这里，我们结合了生物学和信息学分析，包括RNAseq，蛋白质检测，ATACseq和条件性基因缺失，以预测转录调节因子（TR），这些转录调节因子在小鼠和人类的各种CNS疾病中差异控制超过12，000种潜在的星形胶质细胞反应性DEG。星形胶质细胞反应性DEG在各种疾病中表现出明显的异质性。TR也表现出疾病特异性差异，但61个TR的核心组被确定为在两个物种中的多种疾病中是常见的。我们的实验表明，DEG多样性是由组合的，上下文特定的TR相互作用，特别是：相同的反应性TR可以调节显着不同的DEG队列在不同的疾病; TR DNA结合基序访问的变化显着不同的疾病; DEG的变化可以至关重要地需要多个反应性TR。我们表明，调节反应性TRs可以有力地改变疾病的结果，暗示他们作为治疗靶点。我们提供了可搜索的资源，疾病相关的反应性星形胶质细胞DEG和他们的预测TR。我们的研究结果表明，与星形胶质细胞反应性相关的转录变化是非常异质的，并通过上下文特异性组合TR相互作用从大量潜在的DEG定制。
Astrocytes respond to all central nervous system (CNS) insults with reactive changes that influence disorder outcome. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here, we combined biological and informatic analyses including RNAseq, protein detection, ATACseq and conditional gene deletion, to predict transcriptional regulators (TRs) that differentially control over 12,000 potential astrocyte reactivity DEGs across diverse CNS disorders in mice and humans. Astrocyte reactivity DEGs exhibited pronounced heterogeneity across disorders. TRs also exhibited disorder-specific differences, but a core group of 61 TRs was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific TR interactions, notably: the same reactivity TRs can regulate markedly different DEG cohorts in different disorders; TR DNA-binding motif access changes differ markedly across disorders; DEG changes can crucially require multiple reactivity TRs. We show that modulating reactivity TRs can powerfully alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted TRs. Our findings show that transcriptional changes associated with astrocyte reactivity are exquisitely heterogeneous and are customized from vast numbers of potential DEGs via context-specific combinatorial TR interactions.
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影响因子：
6.2
作者：
Cui, Min;Huang, Yunlong;Tian, Changhai;Zhao, Yong;Zheng, Jialin
通讯作者：
Zheng, Jialin
影响因子：
4.4
作者：
Deschamps S;Crow JA;Chaidir N;Peterson-Burch B;Kumar S;Lin H;Zastrow-Hayes G;May GD
通讯作者：
May GD
影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
4.8
作者：
DIEHL, JA;TONG, W;HANNINK, M
通讯作者：
HANNINK, M