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Biochemical and biophysical research communications v.494 no.3/4, 2017년, pp.470 - 476   SCI SCIE
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JAK2V617F influences epigenomic changes in myeloproliferative neoplasms

Chen, Chih-Cheng (Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Chang Gung University College of Medicine, Taoyuan, Taiwan ); Chiu, Chia-Chen (Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Chang Gung University College of Medicine, Taoyuan, Taiwan ); Lee, Kuan-Der (Division of Hematology and Oncology, Department of Medicine, Taipei Medical University Hospital, Taipei, Taiwan ); Hsu, Chia-Chen (Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Chang Gung University College of Medicine, Taoyuan, Taiwan ); Chen, Hong-Chi (Department of Life Science and Gene Therapy Division, Tzu-Chi University and Hospital, Hualien, Taiwan ); Huang, Tim H.-M. (Cancer Therapy and Research Center, Department of Molecular Medicine and Institute of Biotechnology, School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA ); Hsiao, Shu-Huei (Human Epigenomics Center, Department of Life Science, Institute of Molecular Biology and Institute of Biomedical Science, National Chung Cheng University, ); Leu, Yu-Wei ( );
  • 초록  

    Abstract Negative valine (V) to phenylalanine (F) switch at the Janus kinase (JAK2) 617 codon (V617F) is the dominant driver mutation in patients with myeloproliferative neoplasms (MPNs). JAK2V617F was proved to be sufficient for cell transformation; however, independent mutations might influence the following epigenomic modifications. To assess the JAK2V617F-induced downstream epigenomic changes without interferences, we profiled the epigenomic changes in ectopically expressed JAK2V617F in Ba/F3 cells. Antibodies against phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and enhancer of zeste homolog 2 (EZH2) were used for chromatin-immunoprecipitation sequencing (ChIP-seq) to detect the downstream epigenomic targets in the JAK2–STAT3 signaling pathway. To confirm the JAK2V617F-induced epigenetic changes in vivo , DNA methylation changes in the target loci in patients with MPNs were detected through methylation-specific polymerase chain reaction and were clustered against the changes within controls. We found that ectopically expressed JAK2V617F in Ba/F3 cells reduced the binding specificity; it was associated with cis -regulatory elements and recognized DNA motifs in both pSTAT3-downstream and EZH2-associated targets. Overlapping target loci between the control and JAK2V617F were FOXH1, HOXC9 , and SRF ) were clustered independently from the control locus ( L1TD1 ) and other mutation genes ( HMGA2 and Lin28A ) in the analyzed MPN samples. Therefore, JAK2V617F influences target binding in both pSTAT3 and EZH2. Without mutations in epigenetic regulators, JAK2V617F can induce downstream epigenomic modifications. Thus, epigenetic changes in JAK2 downstream targets might be trackable in vivo . Highlights Ectopically expressed JAK2V617F in Ba/F3 cells reduced the binding specificity of pSTAT3- and EZH2-associated targets. JAK2V617F can induce downstream epigenomic modifications. The methylation changes in the JAK2-STAT3 target loci were clustered differently from the control and other mutation genes.


  • 주제어

    Epigenetics .   DNA methylation .   V617F mutation .   Myeloproliferative neoplasms.  

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