Exploring Sex Difference in Epigenetic and Transcription Regulatory MechanisMS Underlying Neuroglial and Behavioral Plasticity in the Prenatal Stress-Induced Mouse Model of Depression

Abstract

Depression is a debilitating neuropsychiatric disorder predicted to be the leading cause of disability by 2035 as per WHO, yet the underlying molecular mechanisms are unknown. Prenatal or gestational stress has a major contribution to many neuropsychiatric disorders, including depression. Here we have tried to study the effects of prenatal stress on the offspring’s hippocampus in late adulthood. We used animal behavior paradigms to assess the anxiety and depression like phenotypes and indeed we were able to observe mood disorder phenotype in male offsprings and not in females. Our intense real time PCR studies to understand the epigenetic regulators involved in underlying neurobehavioural changes, specifically histone H3 and H4 lysine demethylases and lysine methyl trasferases. Western blot studies for assessing global changes in methylation specific epigenetic marks led us to uncover significant change in H3K4me3, H3K9me1 and H4K20me1, along with change in the transcript levels of demethylases/methyltransferases responsible for demethylating/methylating histone lysines. Previous lab microarray data had indicated alteration in some forkhead family transcription factors in hippocampus in sex biased manner. Here we successfully validated Foxb2 and Foxh1 in gender-specific manner. Further, our ChIP-qPCR analysis showed differential enrichment of Foxb2 on promoters of Sox2, Nestin and Synaptotagmin genes, the neurogenesis and neuroplasticity markers. Irrespective of the enrichment at the promoter region of genes that control neurogenesis, these genes were found upregulated in female while unaltered in male hippocampus. So from these novel data it is difficult to elucidate role of FoxB2 in neurogenesis; more studies are required to get better insight.