Dissecting genetic determinants of transcription factor activity

Abstract

Understanding how phenotype relates to genotype, in terms of the myriad molecular processes that govern the behavior of cells and organisms, has been one of the central goals of biology for a long time. Transcription factors (TFs) play a mediating role connecting genotype with gene expression, which provides high-dimensional information about end phenotype. In particular, gene expression levels depend on their cis-regulatory sequence bound by TFs and condition-specific regulatory activity of TFs determined by its modulators through interaction with cofactors or signaling molecules. This thesis consists of two parts that related to the overall goal of dissecting upstream modulators of transcription factor activity. The first study is to dissect genetic determinants of transcription factor activity in a segregating population. We exploit prior knowledge about the in vitro DNA-binding specificity of a TF in order to map the loci (`aQTLs') whose inheritance modulates its protein-level regulatory activity. The second study is to identify regulatory mechanisms underlying tumorigenesis in mice by using genotyping and gene expression data across a set of 97 splenic tumors induced by retroviral insertional mutagenesis. We identify several instances of sequence-specific TFs whose activities are specifically affected by insertions mutations. Our results underscore the value of explicitly modeling TF activity and a strategy for finding upstream modulators of TF activity