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Open Access Publications from the University of California

Identifying and Dissecting Regulatory Elements that Drive Drug Response and Human Evolution

  • Author(s): Ryu, Ann Hane
  • Advisor(s): Ahituv, Nadav
  • et al.
Abstract

Gene regulation is known to contribute to the wide diversity of biological differences between cell types, individuals, and species. Enhancers are regulatory elements that determine when, where, and how much a protein-coding gene is expressed in every tissue. They contain short motifs called transcription factor binding sites and function through chromatin remodeling and DNA looping to activate transcription of their target genes. Due to their role in activating gene expression across tissues and developmental timepoints, disruption in enhancer function can lead to disease and morphological differences between species. By characterizing enhancers we can learn how genetic changes in non-coding DNA alter gene function and ultimately use this knowledge to diagnose and treat disease.

Using RNA-sequencing and chromatin immunoprecipitation (ChIP) sequencing, I identified genome-wide antibiotic-induced changes in gene expression and regulation in HepG2 cells, a human liver cell line. More specifically, I found 209 genes responsive to penicillin-streptomycin (PenStrep), a commonly used cell culture antibiotic cocktail, and 9,514 H3K27ac peaks that were PenStrep-responsive. I also performed a massively parallel reporter assay (MPRA) to quantify enhancer activity of conserved DNA elements that have rapidly evolved in humans called human accelerated regions (HARs) in human and chimpanzee iPSC-derived neural and glial progenitor cells. This method allowed us to detect novel brain enhancers with species-specific function and dissect the regulatory architecture of these enhancers. Our results showed that the cis features or sequence level changes were greater drivers of differences in enhancer activity than the trans environment, or cell species and cell stage, that these sequences were tested in. My research sheds insight on the regulatory code driving drug response to common antibiotics, as well as the uniquely human patterns in early neurodevelopment.

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