JAK2V617F influences epigenomic changes in myeloproliferative neoplasms
| Autor: | Yu-Wei Leu, Tim H M Huang, Shu-Huei Hsiao, Chia-Chen Hsu, Chih-Cheng Chen, Chia Chen Chiu, Kuan Der Lee, Hong Chi Chen |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Epigenomics
STAT3 Transcription Factor 0301 basic medicine Biophysics Biology medicine.disease_cause Biochemistry Epigenesis Genetic Mice 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor medicine Animals Enhancer of Zeste Homolog 2 Protein Epigenetics Molecular Biology Mutation Myeloproliferative Disorders EZH2 Cell Biology Janus Kinase 2 Molecular biology 030104 developmental biology chemistry Hematologic Neoplasms DNA methylation STAT protein Janus kinase DNA |
| Zdroj: | Biochemical and Biophysical Research Communications. 494:470-476 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2017.10.108 |
| Popis: | 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 were3% and 0.4%, respectively, as identified through pSTAT3 and EZH2 ChIP-seq. Furthermore, the methylation changes in the direct target loci (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. |
| Databáze: | OpenAIRE |
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