UCSF

Gene regulation can contribute to phenotypic divergence across species and cell types. By comparing regulatory regions between cell types and between species we can gain an understanding of how sequence changes affect gene regulation and ultimately organismal phenotypes and disease. Using computational methods, I quantified motif enrichment between sets of enhancers in order to characterize functional differences. I was able to identify transcription factors that showed a significant difference in the number of motifs enriched in homologous mouse and human cardiomyocyte enhancers. I also identified differentially enriched transcription factor motifs in embryonic stem cells and differentiated cardiomyocytes. These same methods were also applied to a third dataset in order to detect differences between binding sites that were unique to mutant SOX2 and binding sites that were shared between wildtype and mutant SOX2 binding sites. I found significant depletion of the OCT4:SOX2 motif in mutant SOX2 binding sites. In addition to this, my work also used a comparative genomics approach to identify regions that evolved rapidly in the bat ancestor, but are highly conserved in other vertebrates. I discovered 166 bat accelerated regions (BARs) that overlap epigenetic marks in developing mouse limbs and validated their function in limb development. Of particular note was an enhancer near the HoxD cluster that shows forelimb specific expression in bats compared to mice.