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Ko M Huang Y Jankowska AM Pape UJ Tahiliani M Bandukwala HS An J Lamperti ED Koh KP Ganetzky R Liu XS Aravind L Agarwal S Maciejewski JP Rao A 《Nature》2010,468(7325):839-843
TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. 相似文献
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A gene expression map of Arabidopsis thaliana development 总被引:3,自引:0,他引:3
Schmid M Davison TS Henz SR Pape UJ Demar M Vingron M Schölkopf B Weigel D Lohmann JU 《Nature genetics》2005,37(5):501-506
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Since the completion of the sequencing of the human genome, scientific focus has shifted from studying genes to analysing the much larger number of proteins encoded by them. Several proteins can be generated from a single gene depending on how the genetic information is read (transcribed) and how the resultant protein is modified following translation (post-translational modification). Genomic and proteomic technologies are already providing useful information about autoimmune disease, and they are likely to lead to important discoveries within the next decade. 相似文献
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Pastor WA Pape UJ Huang Y Henderson HR Lister R Ko M McLoughlin EM Brudno Y Mahapatra S Kapranov P Tahiliani M Daley GQ Liu XS Ecker JR Milos PM Agarwal S Rao A 《Nature》2011,473(7347):394-397
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