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Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms

By Mueller Nancy, Maeda Michiyuki, Yasunaga Jun-ichirou, Nosaka Kisato, Taniguchi Yuko, Okayama Akihiko and Matsuoka Masao


<p>Abstract</p> <p>Background</p> <p>Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) after a long latent period. Among accessory genes encoded by HTLV-I, the <it>tax </it>gene is thought to play a central role in oncogenesis. However, Tax expression is disrupted by several mechanims including genetic changes of the <it>tax </it>gene, deletion/hypermethylation of 5'-LTR. To clarify the role of epigenetic changes, we analyzed DNA methylation and histone modification in the whole HTLV-I provirus genome.</p> <p>Results</p> <p>The <it>gag</it>, <it>pol </it>and <it>env </it>genes of HTLV-I provirus were more methylated than pX region, whereas methylation of 5'-LTR was variable and 3'-LTR was not methylated at all. In ATL cell lines, complete DNA methylation of 5'-LTR was associated with transcriptional silencing of viral genes. HTLV-I provirus was more methylated in primary ATL cells than in carrier state, indicating the association with disease progression. In seroconvertors, DNA methylation was already observed in internal sequences of provirus just after seroconversion. Taken together, it is speculated that DNA methylation first occurs in the <it>gag</it>, <it>pol </it>and <it>env </it>regions and then extends in the 5' and 3' directions <it>in vivo</it>, and when 5'-LTR becomes methylated, viral transcription is silenced. Analysis of histone modification in the HTLV-I provirus showed that the methylated provirus was associated with hypoacetylation. However, the <it>tax </it>gene transcript could not be detected in fresh ATL cells regardless of hyperacetylated histone H3 in 5'-LTR. The transcription rapidly recovered after <it>in vitro </it>culture in such ATL cells.</p> <p>Conclusion</p> <p>These results showed that epigenetic changes of provirus facilitated ATL cells to evade host immune system by suppressing viral gene transcription. In addition, this study shows the presence of another reversible mechanism that suppresses the <it>tax </it>gene transcription without DNA methylation and hypoacetylated histone.</p

Topics: Medicine (General), R5-920, Medicine, R, DOAJ:Medicine (General), DOAJ:Health Sciences, Immunologic diseases. Allergy, RC581-607
Publisher: BioMed Central
Year: 2005
DOI identifier: 10.1186/1742-4690-2-64
OAI identifier:
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