Social regulation of transcription and methylation networks in the brain

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): Social relationships are an essential part of human well-being and can affect health in both positive and negative ways, but the underlying biological mechanisms are not well understood. A better understanding of the genetic and epigenetic systems that underlie social behavior would improve diagnosis and treatment of neuropsychiatric disorders that are characterized by deficits in social cognition and behavior. For example, autism spectrum disorders, schizophrenia, and depression share problems of social interactions. Epigenetic modifications of gene expression have been implicated in these disorders, including with respect to sex steroid action, likely reflecting the gender differences i their prevalence. Vertebrate social behavior is coordinated by conserved networks of neural circuits collectively known as the social behavior network, which includes the preoptic, anterior, and ventromedial subregions within the hypothalamus. Astatotilapia burtoni, an African cichlid fish, is a well-established model system for understanding how social behavior changes the brain. Males exist as one of two socially controlled, reversible, phenotypes with rich, quantifiably distinct behavioral repertoires: reproductively competent dominant (D) males and reproductively incompetent non-dominant (ND) males. Previous studies have identified differences in gene expression and DNA methylation in A. burtoni hypothalamus as a function of social status. The proposed study will greatly extend prior efforts by taking advantage of next-generation sequencing technologies to generate gene expression data and genome-wide DNA methylation maps from the hypothalamus of A. burtoni males recently ascended from ND to D status, comparing animals with and without a steroid blocker. This pharmacological intervention will illuminate key steroid effects on behavior via gene transcription. A biologically inspired and constrained network-based analysis framework will integrate molecular information with behavioral and physiological data from the same fish in an unbiased manner. The specific goals will be to identify large-scale gene expression and methylation patterns that are important for altering social behavior, and to test hypotheses about how transcriptional effects downstream of steroid action drive behavioral and physiological changes related to social status. Gene ontology analysis will characterize functions of groups of genes co-regulated by social context, and identify sequence features (e.g. transcription factor binding sites) that suggest common regulatory mechanisms. Results will be used to design mechanistic follow-up studies. Overall, the results will refine our general understanding of the relationships between gene expression, epigenetic regulation, and the social environment, as well as identify specific connections between molecular systems and social behaviors. This research will also provide insight into the interplay between gene expression and methylation as it pertains to disease and the evolution of social behavior.