Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species'

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A central challenge in modern genomics is to decipher how DNA sequence encodes regulatory information, and how this is interpreted by trans-acting factors to produce cell type-specific programs of gene expression. We propose to use a variety of approaches and model systems to elucidate the genomic mechanisms that control spatially and temporally dynamic gene expression programs. To do so, we will use our recently established panels of induced pluripotent stem cells (iPSCs) from humans and chimpanzee, which allow us to perform dynamic and high-resolution studies of different gene regulatory phenotypes. We focus on addressing three complementary questions that allow us to study gene regulation using different perspectives: (i) Using evolutionary perspective, we ask what are the genetic and regulatory differences between humans and non-human apes? (ii) Using population perspective, we ask how do genetic changes in regulatory elements result in inter-individual differences in transcript and protein expression levels? (iii) Finally, focusing on a fundamental property of gene regulation, which until recently we were unable to study because of lack of suitable technology: We ask what is the genetic and mechanistic basis for the regulation of gene expression noise and robustness?