Biochemistry and Molecular Pharmacology
Program in Biochemistry and Molecular Pharmacology
First Thesis Advisor
Tariq M. Rana
Positive Transcriptional Elongation Factor B, RNA Polymerase II, Transcription Factors, HIV-1
RNA polymerase II-mediated transcription of HIV-1 genes depends on positive transcription elongation factor b (P-TEFb), the complex of cyclin T1 and CDK9. Recent evidence suggests that regulation of transcription by P-TEFb involves chromatin binding and modifying factors. To determine how P-TEFb may connect chromatin remodeling to transcription, we investigated the relationship between P-TEFb and histone H1. We show that P-TEFb interacts with H1 and that H1 phosphorylation in cell culture correlates with P-TEFb activity. Importantly, P-TEFb also directs H1 phosphorylation during Tat transactivation and wild type HIV-1 infection. Our results also show that P-TEFb phosphorylates histone H1.1 at a specific C-terminal site. Expression of a mutant H1.1 that cannot be phosphorylated by P-TEFb disrupts Tat transactivation as well as transcription of the c-fos and hsp70 genes in HeLa cells. P-TEFb phosphorylation of H1 also plays a role in the expression of muscle differentiation marker genes in the skeletal myoblast cell line C2C12. Additionally, ChIP experiments demonstrate that H1 dissociates from the HIV-1 LTR in MAGI cells, stress-activated genes in HeLa cells, and muscle differentiation marker genes in C2C12 cells under active P-TEFb conditions. Our results overall suggest a new role for P-TEFb in both cellular and HIV-1 transcription through chromatin.
O'Brien S. (2010). Regulation of Cellular and HIV-1 Gene Expression by Positive Transcription Elongation Factor B: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/yvpr-mx32. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/528
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