Genomic Analysis into Transcriptional Regulation of Cell Identity - Project Summary/Abstract
Every single cell in an organism has almost the exact same genomic information, yet cells in the body
develop into vastly different cell identities. For example, how does one cell become a liver cell and
another cell become a skin cell? This terminal differentiation into distinct cell types is due to correct
transcriptional regulation for that cell type. Transcription factors (TFs) are regulatory proteins that bind
to specific sequences of DNA, response elements, to turn on or off genes for that cell type. Throughout
development, TFs navigate the chromatin landscape of the cell and bind response elements,
integrating physiological and gene-specific cues, directing precise gene regulatory networks. Critical to
TF action is recognition of the correct response element and subsequent regulation to its appropriate
target gene, while not affecting the neighboring genes’ regulation. However, how a TF recognizes the
correct response element and target gene is not well understood. Mutations in TFs and their response
elements result in a wide array of human diseases, thus understanding these basic mechanisms of
transcription factor fidelity is critical to our understanding of human health. Our long-term goal is to
characterize the mechanism of TF response element recognition and target gene recognition in
dinstinct cell types. C. elegans provides a unique opportunity to study TF regulation due to its
compact genome. Intergenic distance in C. elegans is on average 2 Kbp, which allows for easier
correlation of response element to target gene due to the reduced genomic complexity while likely
requiring efficient mechanism to shield aberrant TF action. In this proposal we use a well-studied
nuclear hormone receptor, NHR-25, with two mammalian orthologs, NR5A1/SF-1 and NR5A2/SF-2, to
interrogate TF binding and cell-type specific target gene regulation. We will do so through a
combination of genomic and genetic techniques, exploiting new genome editing methods, chromatin
binding assays, and unique genomic features of C. elegans. These experiments will provide insight into
how TFs recognize their response element and target gene while training undergraduate scientists in
cutting-edge, genomic techniques.
