In silico prediction of regulators of neuronal identity through phylogenetic footprinting

Abstract

How individual neurons in a nervous system give rise to complex function, behavior and consciousness in higher animals has been studied for over a century, yet scientist have only begun to understand how brains work at the molecular level. This level of study is made possible through technological advances, especially transgenic analysis of the cells that make up nervous systems. To date, no other system has been used as extensively as the nematode Caenorhabditis elegans in this pursuit. With just 302 neurons in the adult hermaphrodite, extensive neuronal maps at the anatomical, functional, and molecular level have been built over the past 30 years. One way to understand how nervous systems develop and differentiate into diverse cell types such as sensory or motor neurons that make higher level behaviors possible, is to unravel the underlying gene regulatory programs that control development. Throughout my PhD I investigated neuron type identity regulators to understand how nervous system diversity is generated and maintained using several bioinformatic approaches. First, I developed a software program and community resource tool, TargetOrtho, useful for identifying novel regulatory targets of transcription factors such as the cell type selector proteins termed terminal selectors evidenced to control terminal cell identity of 74 of the 118 neuron types in C. elegans. Analysis of terminal selector candidate target genes led to the further discovery that predicted target genes with cis-regulatory binding sites are enriched for neuron type specific genes suggesting an overarching theme of direct regulation by terminal selectors to specify cell type. Using this knowledge, I make predictions for novel regulators of neuronal identity to further elucidate how the C. elegans nervous system diversifies into 118 neuron types