Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors.
Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors.
复制标题
DOI：
10.1038/s41467-021-24967-z
复制
发表时间：
2021-08-06
影响因子：
16.6
通讯作者：
Reul JMHM
中科院分区：
文献类型：
--
作者：
Mifsud KR;Kennedy CLM;Salatino S;Sharma E;Price EM;Haque SN;Gialeli A;Goss HM;Panchenko PE;Broxholme J;Engledow S;Lockstone H;Cordero Llana O;Reul JMHM
糖皮质激素（GC）-通过海马盐皮质激素受体（MR）和糖皮质激素受体（GR）起作用-对生理调节和行为适应至关重要。我们对大鼠海马进行了全基因组MR和GR ChIP-seq和Ribo-Zero RNA-seq研究，以阐明昼夜节律变化或急性应激下MR和GR调节的基因。在基因的子集中，这些生理条件导致增强的MR和/或GR与DNA序列的结合以及相关的转录变化。然而，MR在大量位点的结合保持不变。MR和GR结合发生在重叠以及不同的位点。此外，虽然GC反应元件（GRE）是主要的基序，MR和GR结合峰内的转录因子识别位点的组成显示出显着的差异。通路分析发现，MR和GR调节突触/神经可塑性，细胞形态和发育，行为和神经精神疾病中涉及的大量基因。我们发现，MR，而不是GR，是结合到>50纤毛基因的主要受体;并且MR功能与人胎儿神经元祖细胞中的神经元分化和纤毛发生有关。这些结果表明，海马MR和GR组成和动态调节基因组活动的神经元可塑性和行为适应不断变化的环境。糖皮质激素（GC）对维持大脑健康至关重要，但对它们与精神障碍的关系知之甚少。在这里，作者展示了GCs如何通过海马盐皮质激素和糖皮质激素受体来影响支持神经元可塑性、纤毛发生和行为适应的基因调控程序。
Glucocorticoid hormones (GCs) — acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) — are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments. Glucocorticoid hormones (GCs) are of critical importance for maintaining brain health, but their involvement in mental disorders is poorly understood. Here the authors show how GCs act through hippocampal mineralocorticoid and glucocorticoid receptors to impact the gene regulatory programs underpinning neuronal plasticity, ciliogenesis and behavioral adaptation.
登录
查看更多内容
影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
糖皮质激素受体在巨噬细胞中协调转录因子主导的调节网络。
影响因子：
4.4
作者：
Chinenov Y;Coppo M;Gupte R;Sacta MA;Rogatsky I
通讯作者：
Rogatsky I
影响因子：
4.1
作者：
Burd, Craig J.;Archer, Trevor K.
通讯作者：
Archer, Trevor K.
影响因子：
3.3
作者：
Chen, Hui;Amazit, Larbi;Le Menuet, Damien
通讯作者：
Le Menuet, Damien
影响因子：
2.9
作者：
Cordero, MI;Sandi, C
通讯作者：
Sandi, C