The Role of Egr1 in Driving Sex-Specific Transcriptional Programs and Anxiety-Related Behavior
Women have a two-fold increased risk for anxiety and depression disorders compared to men, though the molecular mechanisms underlying this phenomenon are understudied. Clinical and epidemiological data indicate ovarian hormone fluctuations are a critical female-specific risk factor for these disorders. Accordingly, we previously demonstrated that anxiety-like behavior in female mice varies across the estrous cycle. We also showed estrous cycle-dependent changes in neuronal chromatin accessibility and gene expression in the ventral hippocampus, a region critical for emotion regulation in rodents. Analysis of these data identified Egr1, a transcription factor and estrogen-responsive immediate early gene product, as a candidate regulator of chromatin regulation and gene expression across the estrous cycle. To test this, in the current study, I first profiled behavior and Egr1 expression across the four estrous cycle phases, revealing that high-estrogenic proestrus females have lower anxiety indices. However, following the withdrawal of estrogen levels that characterizes the other phases, anxiety-related behavior increased. In parallel, I observed cycling Egr1 mRNA expression across the estrous cycle, following estrogen levels. To mechanistically link Egr1 to the estrous cycle-dependent behavioral and molecular phenotype, I performed AAV-mediated, neuronal-specific overexpression of Egr1 in the ventral hippocampus of intact-male and ovariectomized-female mice. I then performed anxiety- and depression-related behavioral tests, as well as cell type-specific genomics assays profiling neuronal chromatin (ATAC-seq) and gene expression (RNA-seq). Results from behavioral tests implicate Egr1 in driving cyclical changes in anxiety- and depression-related behaviors in females, with no effect of Egr1 overexpression in males, indicating the effect is sex-specific. Further, Egr1 overexpression induced sex-specific changes in gene expression and chromatin organization, including Egr1-directed chromatin opening, in ventral hippocampal neurons that give crucial insights into this behavioral phenotype, including female-specific regulation of genes related to serotonin and anxiety. Overlapping these data with the previously generated estrous cycle data demonstrated that Egr1-induced chromatin regulation facilitates the downregulation of anxiety-related genes and the upregulation of synaptic plasticity-related genes during the high-estrogenic proestrus phase. Taken together, these results causally link Egr1 to estrous cycle-dependent gene regulation and behavioral plasticity and establish a foundation for developing sex-specific treatments for anxiety and depression.
Neurosciences|Behavioral Sciences|Genetics|Womens studies
Rocks, Devin, "The Role of Egr1 in Driving Sex-Specific Transcriptional Programs and Anxiety-Related Behavior" (2023). ETD Collection for Fordham University. AAI30633271.