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Date of Graduation
Master of Science (MS)
Dr. Casonya Johnson
The HES family of transcription factors are primarily repressors of transcription that play critical roles in mammalian embryogenesis by regulating cell differentiation and proliferation. Proper functioning of HES proteins is crucial in humans, as mutations or misexpression of HES1 is associated with lung, pancreas, colon, and other cancers. HES1 may mediate short-range or long-range repression through DNA-binding and or protein-protein interactions with other factors. However, prior genetic studies have not fully elucidated how the context-specific binding of HES1, or its C. elegans ortholog HLH-25, promotes the repression of transcription. Characterization of the cis-regulatory context and mechanism of HLH-25 mediated repression could thus serve as a model for studying the role of HES1 in disease. In the present study, we used an RNA-sequencing based approach to identify differentially expressed genes (DEGs) by comparing the early embryonic transcriptomes of wildtype (N2) and hlh-25 and hlh-27 double knockout animals. Gene ontology analysis of the DEGs demonstrates that HLH-25 regulates genes that are involved in essential cellular roles such as metabolism, DNA-repair, chemosensation, and transmembrane transport. Computational mapping of HLH-25 to transcriptional regulatory elements of its embryonic gene targets shows preferential binding of the transcription factor at cis-regulatory elements located distal to transcription start sites, in a consistent manner across genes with different biological roles. Taken together, our findings suggest that the most likely mechanism for gene-specific repression by HLH-25 is through a distally-bound long-range repressive activity of recruiting histone deacetylases or remodeling chromatin at or near the promoter.
Mamo, Dagmawi, "Understanding the regulatory context and mechanism of HLH-25 mediated transcriptional repression" (2023). Masters Theses, 2020-current. 235.
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