IMG 0745

Current Research

Retroviruses serve as outstanding model systems for the study of gene regulation in a chromatin context in higher eukaryotes. Following infection, the retroviral genome stably and permanently integrates into a host-cell chromosome. During this process, the proviral DNA is assembled into nucleosomal arrays that package and compact the viral genome. In this chromatin state, the provirus is indistinguishable from a cellular gene and is regulated in an analogous manner. Because chromosomal integration is an obligatory event in the retroviral life cycle, these viruses have evolved a highly efficient mechanism to potently activate transcription (and thus viral replication) from the compacted chromatin state. The human T-cell leukemia virus, type 1 (HTLV-1) is a well-established model system for both in vivo and in vitro studies on transcriptional activation in a chromatin context. This retrovirus is of medical interest, as it is responsible for a number of dissimilar diseases. These include Adult T-cell Leukemia/Lymphoma and Tropical Spastic Paraparesis, an inflammatory condition that is clinically and pathologically analogous to multiple sclerosis. The HTLV-1-encoded Tax protein plays an essential role in the etiology of both diseases, and is an extraordinarily potent activator of transcription.

Tax strongly stimulates HTLV-1 transcription, as well as the transcription of numerous cellular genes. As such, Tax is an outstanding model activator protein to study gene expression in higher eukaryotes. We recently developed a chromatin-based in vitro transcription system to better understand general mechanisms of gene activation in the context of chromatin. Tax was a critical component in the successful development of this in vitro chromatin-based transcription system as the protein likely evolved, in part, to mediate the transition of the provirus from a chromatin-dense repressed state into a relaxed, transcriptionally active state.    

To achieve this transition, Tax works in concert with the phosphorylated form of the cellular protein CREB (pCREB). Together, both proteins bind the HTLV‑1 promoter at an enhancer composed of three conserved 21 bp repeats that carry unique cAMP response elements, called viral CREs (vCREs). This elegant assemblage of proteins at the HTLV-1 promoter serves to recruit the ubiquitous and multifunctional cellular coactivators p300/CBP. Together, the Tax/ pCREB/p300 complex promotes strong tran­scrip­tional activation in vitro   

HTLV1 Genome

The Nyborg Lab at Colorado State University © 2012