Negative regulation of JAK2 by H3K9 methyltransferase G9a in leukemia.
Histone methylation at specific lysine residues is a crucial regulatory process in transcriptional regulation. Using chromatin immunoprecipitation with microarray technology (ChIP-chip) analysis, we found that the H3K9-me2 target gene JAK2 was an important factor during differentiation of the HL-60 promyelocytic leukemia cell line by all-trans-retinoic acid (ATRA) treatment. Here, we report that the H3K9 methyltransferase G9a negatively regulated JAK2 transcription in histone methyltransferase activity and in a YY1-dependent manner during ATRA-mediated leukemia cell differentiation. We found that G9a knockdown repressed ATRA-mediated HL-60 cell differentiation. We demonstrated that G9a interacts with YY1 and is recruited to the JAK2 promoter along with corepressors, including histone deacetylase, that induced H3K9-me2. Repression of JAK2 transcription by G9a decreased H3Y41 phosphorylation and promoted inhibition of the recently identified JAK2-H3Y41P-HP1α pathway-mediated leukemogenesis.
Department of Life Science, College of Natural Sciences, Research Center for Biomolecules and Biophysics, Chung-Ang University, Seoul, Republic of Korea.
Hye-Ju
HJ
Son
Ji-Young
JY
Kim
Yoonsoo
Y
Hahn
Sang-Beom
SB
Seo
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D000090266:Chromobox Protein Homolog 5; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000096:biosynthesis / Q000378:metabolism*; D020014:K562 Cells; D060588:LIM Domain Proteins / Q000235:genetics; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D008745:Methylation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D050986:YY1 Transcription Factor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C000715594:CBX5 protein, human; D006649:Histocompatibility Antigens; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D000090266:Chromobox Protein Homolog 5; D014212:Tretinoin; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; C507924:JAK2 protein, human; D053614:Janus Kinase 2