Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, 85004, USA.
Northeastern University, Toronto, ON, M5X 1E2, Canada.
Transl Psychiatry. 2022 Aug 8;12(1):320. doi: 10.1038/s41398-022-02069-8.
Bioinformatics and network studies have identified the immediate early gene transcription factor early growth response 3 (EGR3) as a master regulator of genes differentially expressed in the brains of patients with neuropsychiatric illnesses ranging from schizophrenia and bipolar disorder to Alzheimer's disease. However, few studies have identified and validated Egr3-dependent genes in the mammalian brain. We have previously shown that Egr3 is required for stress-responsive behavior, memory, and hippocampal long-term depression in mice. To identify Egr3-dependent genes that may regulate these processes, we conducted an expression microarray on hippocampi from wildtype (WT) and Egr3-/- mice following electroconvulsive seizure (ECS), a stimulus that induces maximal expression of immediate early genes including Egr3. We identified 69 genes that were differentially expressed between WT and Egr3-/- mice one hour following ECS. Bioinformatic analyses showed that many of these are altered in, or associated with, schizophrenia, including Mef2c and Calb2. Enrichr pathway analysis revealed the GADD45 (growth arrest and DNA-damage-inducible) family (Gadd45b, Gadd45g) as a leading group of differentially expressed genes. Together with differentially expressed genes in the AP-1 transcription factor family genes (Fos, Fosb), and the centromere organization protein Cenpa, these results revealed that Egr3 is required for activity-dependent expression of genes involved in the DNA damage response. Our findings show that EGR3 is critical for the expression of genes that are mis-expressed in schizophrenia and reveal a novel requirement for EGR3 in the expression of genes involved in activity-induced DNA damage response.
生物信息学和网络研究已经确定早期生长反应基因 3（EGR3）作为转录因子是神经精神疾病患者大脑中差异表达基因的主要调控因子，这些疾病范围从精神分裂症和双相情感障碍到阿尔茨海默病。然而，很少有研究在哺乳动物大脑中鉴定和验证 Egr3 依赖性基因。我们之前已经表明，Egr3 是应激反应行为、记忆和海马长时程抑制所必需的，在小鼠中。为了鉴定可能调节这些过程的 Egr3 依赖性基因，我们在电惊厥（ECS）后对野生型（WT）和 Egr3-/-小鼠的海马进行了表达微阵列分析，这是一种诱导包括 Egr3 在内的早期基因最大表达的刺激。我们发现 69 个基因在 WT 和 Egr3-/- 小鼠中的表达水平存在差异，在 ECS 后一小时。生物信息学分析表明，其中许多与精神分裂症有关，包括 Mef2c 和 Calb2。Enrichr 通路分析显示，GADD45（生长停滞和 DNA 损伤诱导）家族（Gadd45b、Gadd45g）是差异表达基因的主要群体。与 AP-1 转录因子家族基因（Fos、Fosb）和着丝粒组织蛋白 Cenpa 的差异表达基因一起，这些结果表明，Egr3 是活性依赖性表达参与 DNA 损伤反应的基因所必需的。我们的研究结果表明，EGR3 对于在精神分裂症中表达错误的基因的表达至关重要，并揭示了 EGR3 在参与活性诱导的 DNA 损伤反应的基因表达中的新要求。
