Neuronal Activity, TGFβ-Signaling and Unpredictable Chronic Stress Modulate Transcription of Gadd45 Family Members and DNA Methylation in the Hippocampus
Neuronal Activity, TGFβ-Signaling and Unpredictable Chronic Stress Modulate Transcription of Gadd45 Family Members and DNA Methylation in the Hippocampus
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DOI：
10.1093/cercor/bhx095
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发表时间：
2017-08-01
期刊：
影响因子：
3.7
通讯作者：
Vogel, Tanja
中科院分区：
文献类型：
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作者：
Grassi, Daniela;Franz, Henriette;Vogel, Tanja
神经元活动在几种神经和精神疾病中改变。在去极化时，不仅释放神经递质，而且释放细胞因子和信号级联的其他激活剂。解开它们在接受细胞中转录控制的复杂含义将有助于理解特定的中枢神经系统（CNS）病理，并将具有治疗意义。在这项研究中，我们去极化成熟的海马神经元在体外使用氯化钾和揭示增加释放不仅脑源性神经营养因子（BDNF），但也转化生长因子β（TGFB）。神经元活性与BDNF和TGFB一起控制DNA修饰酶的转录，特别是DNA损伤诱导（Gadd）家族的成员，Gadd45a，Gadd45b和Gadd45g。MeDIP之后进行大规模平行测序和转录组分析，显示KCl处理后DNA甲基化较少。精神疾病相关基因，即Tshz1，Foxn3，Jarid2，Per1，Map3k5和Arc在神经元激活时被转录激活和去甲基化。为了分析Gadd45家族成员的错误表达是否与精神疾病相关，我们采用不可预测的慢性轻度应激（UCMS）作为抑郁症的小鼠模型。UCMS导致Gadd45家族成员的表达减少。综上所述，我们的数据表明，Gadd45家族成员是UCMS治疗的新的推定靶点。
Neuronal activity is altered in several neurological and psychiatric diseases. Upon depolarization not only neurotransmitters are released but also cytokines and other activators of signaling cascades. Unraveling their complex implication in transcriptional control in receiving cells will contribute to understand specific central nervous system (CNS) pathologies and will be of therapeutically interest. In this study we depolarized mature hippocampal neurons in vitro using KCl and revealed increased release not only of brain-derived neurotrophic factor (BDNF) but also of transforming growth factor beta (TGFB). Neuronal activity together with BDNF and TGFB controls transcription of DNA modifying enzymes specifically members of the DNA-damage-inducible (Gadd) family, Gadd45a, Gadd45b, and Gadd45g. MeDIP followed by massive parallel sequencing and transcriptome analyses revealed less DNA methylation upon KCl treatment. Psychiatric disorder-related genes, namely Tshz1, Foxn3, Jarid2, Per1, Map3k5, and Arc are transcriptionally activated and demethylated upon neuronal activation. To analyze whether misexpression of Gadd45 family members are associated with psychiatric diseases, we applied unpredictable chronic mild stress (UCMS) as established model for depression to mice. UCMS led to reduced expression of Gadd45 family members. Taken together, our data demonstrate that Gadd45 family members are new putative targets for UCMS treatments.