Abstract
BackgroundHuman 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 tax gene is thought to play a central role in oncogenesis. However, Tax expression is disrupted by several mechanims including genetic changes of the tax 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.ResultsThe gag, pol and env 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 gag, pol and env regions and then extends in the 5' and 3' directions in vivo, 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 tax gene transcript could not be detected in fresh ATL cells regardless of hyperacetylated histone H3 in 5'-LTR. The transcription rapidly recovered after in vitro culture in such ATL cells.ConclusionThese 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 tax gene transcription without DNA methylation and hypoacetylated histone.
Highlights
Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) after a long latent period
Since Tax protein is the major target of cytotoxic T-lymphocytes (CTLs) in vivo, the expression has a negative effect on the survival of ATL cells [7,8,9]
Since the analyses by sodium bisulfite sequencing were time-consuming, we established the combined bisulfite restriction analysis (COBRA) method to detect and analyze DNA methylation in a large number of samples, and compared the results obtained with the two methods
Summary
Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) after a long latent period. During the leukemogenesis by HTLV-I, Tax protein is considered to play a critical role through its pleiotropic actions, which include transactivation of NF-κB, CREB and SRF pathways, transrepression of lck, p18 and DNA polymerase β gene transcriptions, and functional inactivation of p53 and MAD1 [3,4,5,6]. Through these actions, Tax induces the proliferation of HTLV-I infected cells and inhibits their apoptosis, resulting in an increase in the number of infected cells. Such inactivation of Tax expression is considered to allow ATL cells to escape from the host immune system
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