title: Polycomb-dependent epigenetic landscape in adult T-cell leukemia.
abstract: Adult T-cell leukemia-lymphoma (ATL) shows global gene expression alterations that confer cellular characteristics and unfavorable prognosis. However, molecular mechanisms of the sustained expression changes are largely unknown, because there is no study addressing the relationship between landscapes of the gene expression and epigenetic modifications. Here, we analyzed ATL epigenome and integrated it with transcriptome from primary ATL cells and those from corresponding normal CD4(+)T cells to decipher ATL-specific "epigenetic code" that was critical for cell identity. We found that polycomb-repressive complex 2 (PRC2)-mediated trimethylation at histone H3Lys27 (H3K27me3) was significantly and frequently reprogrammed at half of genes in ATL cells. A large proportion of the abnormal gene downregulation was detected at the early stage of disease progression and was explained by H3K27me3 accumulation. The global H3K27me3 alterations involved ATL-specific gene expression changes that included several tumor suppressors, transcription factors, epigenetic modifiers, miRNAs, and developmental genes, suggesting diverse outcomes by the PRC2-dependent hierarchical regulation. Interestingly, a key enzyme, EZH2, was sensitive to promiscuous signaling network including the NF-κB pathway and was functionally affected by human T-cell leukemia virus type I (HTLV-1) Tax. The Tax-dependent immortalized cells showed H3K27me3 reprogramming that was significantly similar to that of ATL cells. Of note, a majority of the epigenetic silencing has occurred in leukemic cells from indolent ATL and also in HTLV-1-infected T cells from asymptomatic HTLV-1 carriers. Because pharmacologic inhibition of EZH2 reversed epigenetic disruption and selectively eliminated leukemic and HTLV-1-infected cells, targeting the epigenetic elements will hold great promise in treatment and prevention of the onset of ATL and HTLV-1-related diseases.
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Dai
authors.initials: D
authors.lastname: Fujikawa
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Shota
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hori
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kurokawa
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Ai
authors.initials: A
authors.lastname: Soejima
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan;
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; and.
authors.forename: Masako
authors.initials: M
authors.lastname: Iwanaga
authors.affiliation: Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan.
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.affiliation: Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, and.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016356:Gene Products, tax; D006657:Histones; D009363:Neoplasm Proteins; C514970:tax protein, Human T-lymphotrophic virus 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2