October 31, 2020

Identification of activity-dependent EGR3 target genes reveals genes associated with DNA damage response and schizophrenia

The immediate early gene transcription factor early growth response 3 (EGR3) has been identified as a master regulator of genes differentially expressed in the brains of patients with neuropsychiatric illnesses ranging from schizophrenia and bipolar disorder to Alzheimers Disease. These studies used bioinformatics approaches that identify networks of gene and proteins. However, few gene targets of EGR3 have actually been identified and validated in the mammalian brain. Our studies in mice have shown that Egr3 is required for stress-responsive behavior, memory, and the form of hippocampal plasticity long-term depression. To identify genes regulated by Egr3 that may play a role in these processes, we conducted an expression microarray on hippocampi from (WT) and Egr3-/- mice following electroconvulsive seizure (ECS), as stimulus that induces maximal expression of immediate early genes including Egr3. We identifies 71 genes that were differentially expressed between the WT and Egr3-/- mice one hour following ECS, a time when we would expect to identify direct targets of EGR3. Bioinformatic analyses showed that many of these are altered in schizophrenia. Ingenuity pathway analysis revealed that the leading category of differentially expressed are members of the GADD45 (growth arrest and DNA-damage-inducible) family (Gadd45b, Gadd45g, and Cdkn1a). Together with members of the AP-1 transcription factor family (Fos, Fosb), and the centromere organization protein Cenpa, that were also identified, these results revealed that Egr3 is required for activity-dependent expression of genes involved in the response to DNA damage. Using quantitative real time PCR (qRT-PCR) we validated key genes in the original RNA samples from male mice as well as in an independent cohort of female mice. Promoter analyses indicate that a number of these genes may be direct targets of EGR3 regulation. Our findings indicated that EGR3 as a critical regulator of genes that are disrupted in schizophrenia and reveal a novel role for EGR3 in regulating genes involved in activity-induced DNA damage response.

 bioRxiv Subject Collection: Neuroscience

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