Human T-cell leukemia virus alters the epigenetic landscape and core regulatory circuitry in infected cells
Azusa Tanaka1, Jun-ichirou Yasunaga2, Masao Matsuoka2*, Akihiro Fujimoto1*
1Graduate Schools of Medicine, Kyoto University; 2Institute for Frontier Life and Medical Science, Kyoto University
It is now accepted that the initiation and progression of cancer, traditionally seen as a genetic disease, also involves epigenetic aberrations. Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus and the etiological agent of adult T-cell leukemia-lymphoma (ATL). Here, we performed ATAC-seq on ATL cell samples and discovered global alterations in the chromatin status. To characterize differences in chromatin accessibility in ATL cells and normal human CD4+ memory T cells, we searched for regions of gained and lost genome accessibility. Motif analysis of increased accessible sites in ATL cells identified a strong enrichment in TF binding sites including FOXP1, RUNX2, and BATF, which are associated with leukemia.
We next looked at candidate HTLV proteins that may contribute to chromatin changes in infected cells. The HTLV-1 bZIP factor (HBZ), encoded by the minus strand of the provirus, is involved in both the regulation of viral gene transcription and T-cell proliferation. By analyzing H3K27ac chromatin immunoprecipitation of mouse CD4+ T cells with and without HBZ, we found that HBZ dramatically changed typical enhancer and super-enhancer signatures. Furthermore, Foxp1 functioned as a component of the core regulatory circuitry only when HBZ was transduced. These results suggest that HBZ changes the chromatin landscape, thereby allowing FOXP1 to function as a key player in HTLV-1 infected cells. The resulting chromatin changes alter the core regulatory circuitry in infected cells and leads to the initiation and development of leukemia. In the future, we plan to perform single-cell ATAC-seq to explore the variation in chromatin accessibility both between and within populations of single ATL cells.
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