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The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression

机译：BDNF和NPAS4基因是HDAC3介导的转录抑制的靶标

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Histone deacetylase-3 (HDAC3) promotes neurodegeneration in various cell culture and in vivo models of neurodegeneration but the mechanism by which HDAC3 exerts neurotoxicity is not known. HDAC3 is known to be a transcriptional co-repressor. The goal of this study was to identify transcriptional targets of HDAC3 in an attempt to understand how it promotes neurodegeneration. We used chromatin immunoprecipitation analysis coupled with deep sequencing (ChIP-Seq) to identify potential targets of HDAC3 in cerebellar granule neurons. One of the genes identified was the activity-dependent and neuroprotective transcription factor, Neuronal PAS Domain Protein 4 (Npas4). We confirmed using ChIP that in healthy neurons HDAC3 associates weakly with the Npas4 promoter, however, this association is robustly increased in neurons primed to die. We find that HDAC3 also associates differentially with the brain-derived neurotrophic factor (Bdnf) gene promoter, with higher association in dying neurons. In contrast, association of HDAC3 with the promoters of other neuroprotective genes, including those encoding c-Fos, FoxP1 and Stat3, was barely detectable in both healthy and dying neurons. Overexpression of HDAC3 leads to a suppression of Npas4 and Bdnf expression in cortical neurons and treatment with RGFP966, a chemical inhibitor of HDAC3, resulted in upregulation of their expression. Expression of HDAC3 also repressed Npas4 and Bdnf promoter activity. Our results suggest that Bdnf and Npas4 are transcriptional targets of Hdac3-mediated repression. HDAC3 inhibitors have been shown to protect against behavioral deficits and neuronal loss in mouse models of neurodegeneration and it is possible that these inhibitors work by upregulating neuroprotective genes like Bdnf and Npas4.
机译：组蛋白脱乙酰酶-3（HDAC3）促进各种细胞培养物中的神经变性，并且在神经变性的体内模型中，但是HDAC3施加神经毒性的机制是不知道的。已知HDAC3是转录的共压缩机。本研究的目标是识别HDAC3的转录目标，以试图了解它如何促进神经变性。我们使用染色质免疫沉淀分析耦合，与深序（芯片-SEQ）求解，以识别小脑颗粒神经元中HDAC3的潜在靶标。鉴定的其中一种基因是活性依赖性和神经保护转录因子，神经元PAS结构域蛋白4（NPAS4）。我们使用芯片确认，在健康神经元HDAC3与NPAS4启动子弱缔合物，然而，这种关联在初步死亡的神经元中鲁棒地增加。我们发现HDAC3还与脑衍生的神经营养因子（BDNF）基因启动子差异差异，在垂死的神经元中具有更高的关联。相比之下，HDAC3与其他神经保护基因的启动子的关联，包括编码C-FOS，FOXP1和Stat3的那些，在健康和染色的神经元中几乎无法检测到。 HDAC3的过度表达导致抑制皮质神经元中的NPAS4和BDNF表达，并用RGFP966处理HDAC3的化学抑制剂，导致其表达上调。 HDAC3的表达还抑制了NPAS4和BDNF启动子活性。我们的结果表明，BDNF和NPAS4是HDAC3介导的抑制的转录靶标。已经证明HDAC3抑制剂在神经变性的小鼠模型中保护行为缺陷和神经元损失，并且这些抑制剂可能通过上调BDNF和NPAS4等神经保护基因。

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