The effect of chromatin remodeling on transcription of Human T-cell leukemia virus type 1 (HTLV-1)
Open AccessHuman T Lymphotropic virus type 1 (HTLV-1) encodes the viral protein Tax which is believed to act as a viral transactivator through its interactions with a variety of transcription factors such as CREB, NF-kappa B, and others. As is the case for all retroviruses, the provirus is inserted into the host DNA where nucleosomes are deposited to ensure efficient packaging. Nucleosomes act as roadblocks in transcription, making it difficult for RNA polymerase II (Pol II) to proceed toward the 3' end of the genome. Because of this, a variety of chromatin remodelers can act to remodel nucleosomes, allowing for efficient transcription. While a number of covalent modifications are known to occur on histones tails in HTLV-1 infection (i.e. HATs, HDACs, and HMTs), evidence points to the use of chromatin remodelers that use energy from ATP hydrolysis to remodel nucleosomes. Here we confirm that BRG1, which is the core subunit of eight chromatin remodeling complexes, is essential, not only for Tax transactivation, but also in viral replication. This is especially evident when using wild type infectious clones of HTLV-1. BRG1 associates with Tax at the HTLV-1 LTR, and co-expression of BRG1 and Tax results in increased rates of transcription. BRG1's interaction with Tax additionally recruits basal transcriptional machinery and removes some of the core histones from the nucleosome at the start site (nuc 1). When using BRG1 deficient cell lines SW13, C33A, and TSUPR1 we observed little viral transcription and no viral replication. Importantly, while these three cell lines do not express detectable levels of BRG1, much of the SWI/SNF remains assembled in the cells. Knockdown of BRG1 and associated SWI/SNF subunits suggests that the BRG1-utilizing SWI/SNF complex, PBAF, is responsible for HTLV-1 nucleosome remodeling. Finally, HTLV-1 infection in cell lines with a knockdown in BRG1 or PBAF complex results in a significant reduction in viral production. Overall, we concluded that BRG1 is required for Tax transactivation, HTLV-1 viral production, and that the PBAF complex appears to be responsible for nucleosome remodeling.
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