Annotation of human forebrain specific cis-acting gene regulatory networks through Comparative genomics analysis

Abstract

diversification in forebrain during evolution of vertebrates. This (forebrain) section of the central nervous system (CNS) is likely for the tuning of several physiological processes including behavioral responses to external stimuli, vision and olfaction, upholding homeostatic as well as controlling voluntary movement and cognitions. Despite of its multifaceted functions, many disorder are also associated with the cognitive behavior of forebrain often result in vision problems, changes in awareness or behavior, abnormal movements or postures, and seizures. Cis-regulatory networks involved in forebrain diversity have been focus of interest in order to better understand the forebrain morphogenesis and unveil the genetic basis of cognitive diseases. Recently several efforts have been made to generate a genome-wide map of forebrain enhancers by utilizing epigenomic enhancer discovery approaches coupled with transgenic mice assay. Pennacchio and coworkers have reported numerous forebrain specific CNEs and presented them at VISTA enhancer browser after verifying their induced reporter expression pattern. Pennacchio associated these enhancers with the genes harboring them (intragenic) or their nearest flanking genes (intergenic), However an enhancer may not necessarily be regulating the expression of its nearby genes or the genes harboring them, so the present study is an attempt to associate the experimentally verified enhancers by Pennacchio and coworkers (2006 & 2008), to their target genes. In this study, we have exploited 56 functionally defined forebrain CNEs and associated them with their target genes using two techniques; Comparative genomics and Endogenous expression analysis. We associated 12% of 56 CNEs to a single gene, 36 % to two genes, and 34 % to three target genes whereas others were associated to four or more genes. Projected association elucidated in this study indicates that forebrain specific enhancers and transcription factors works in conserved combinatorial gene regulatory mechanism. Enhancers were found to have varied conservation depths from mammals to teleost, depicts the differential evolution of vertebrate’s forebrain. Normally, CNE-enhancer tends to be located in close proximity to their associated target genes however genomic radii analysis of forebrain specific enhancers highlighted that they regulate the expression of their target even at a greater distances