Interaction of HTLV-1 Tax and methyl-CpG-binding domain 2 positively regulates the gene expression from the hypermethylated LTR

Abstract

Epigenetic regulation of gene expression is critical in the maintenance of cellular homeostasis. Dysregulation of normal epigenetic transcription occurs in abnormal physiological conditions, such as those seen in cancer cells and cells infected with parasites, making the mechanism underlying abnormal epigenetic transcription of great interest. Gene expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by a viral transcriptional stimulator, Tax. We herein report a novel mechanism of transcription from the HTLV-1 long terminal repeat (LTR) that is regulated by Tax. In this study, we determined that Tax is able to activate transcription from the LTR, even when it was heavily methylated. In addition, the methyl-CpG-binding domain 2 (MBD2) protein played an important role in Tax-mediated transcriptional activation. We demonstrated the importance of a physical interaction between Tax and MBD2 in enhancing the transcriptional activity of Tax against the methylated LTR. Furthermore, we identified the formation of a protein complex composed of MBD2 and Tax bound to the methylated LTR. We propose a new model of epigenetic regulation by MBD2 acting in concert with a virally encoded transactivator, Tax. Our observation provides insight into the epigenetic regulation of gene expression and the diverse mechanisms of transcriptional regulation using methylated promoters.