Interaction of HTLV-1 Tax and methyl-CpG-binding domain 2 positively regulates the gene expression from the hypermethylated LTR
Interaction of HTLV-1 Tax and methyl-CpG-binding domain 2 positively regulates the gene expression from the hypermethylated LTR
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DOI：
10.1038/sj.onc.1208394
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发表时间：
2005-03-10
期刊：
影响因子：
8
通讯作者：
Shimotohno, K
中科院分区：
文献类型：
--
作者：
Ego, T;Tanaka, Y;Shimotohno, K
基因表达的表观遗传调控在维持细胞内稳态中至关重要。正常表观遗传转录的失调发生在异常的生理条件下，例如在癌细胞和寄生虫感染的细胞中所见的那些，使得异常表观遗传转录的潜在机制引起了极大的兴趣。人类T细胞白血病病毒1型（HTLV-1）的基因表达受病毒转录刺激因子Tax的调控。我们在此报告了一种新的转录机制，从HTLV-1长末端重复序列（LTR），这是由税收调节。在这项研究中，我们确定Tax能够激活LTR的转录，即使它是高度甲基化的。此外，甲基-CpG-结合域2（MBD 2）蛋白在Tax介导的转录激活中发挥重要作用。我们证明了Tax和MBD 2之间的物理相互作用在增强Tax对甲基化LTR的转录活性中的重要性。此外，我们确定了由MBD 2和Tax结合到甲基化LTR的蛋白质复合物的形成。我们提出了一个新的表观遗传调控模型MBD 2与病毒编码的反式激活因子Tax协同作用。我们的观察提供了深入了解基因表达的表观遗传调控和使用甲基化启动子的转录调控的不同机制。
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.