Tet2 Regulates Osteoclast Differentiation by Interacting with Runx1 and Maintaining Genomic 5-Hydroxymethylcytosine (5hmC)
Tóm tắt
As a dioxygenase, Ten-Eleven Translocation 2 (TET2) catalyzes subsequent steps of 5-methylcytosine (5mC) oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hematopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Deletion of Tet2 impairs the differentiation of osteoclast precursor cells (macrophages) and their maturation into bone-resorbing osteoclasts in vitro. Furthermore, Tet2−/− mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cebpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine (5hmC) and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runx1 and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runx1 and the maintenance of genomic 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and treatment of abnormal bone mass caused by the deregulation of osteoclast activities.
Từ khóa
Tài liệu tham khảo
Delhommeau, 2009, Mutation in TET2 in myeloid cancers, N Engl J Med, 360, 2289, 10.1056/NEJMoa0810069
Langemeijer, 2009, Acquired mutations in TET2 are common in myelodysplastic syndromes, Nat Genet, 41, 838, 10.1038/ng.391
Tefferi, 2009, TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis, Leukemia, 23, 905, 10.1038/leu.2009.47
Jankowska, 2009, Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms, Blood, 113, 6403, 10.1182/blood-2009-02-205690
Couronne, 2012, TET2 and DNMT3A mutations in human T-cell lymphoma, N Engl J Med, 366, 95, 10.1056/NEJMc1111708
Asmar, 2013, Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma, Haematologica, 98, 1912, 10.3324/haematol.2013.088740
Meissner, 2013, The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma, Blood, 121, 3161, 10.1182/blood-2013-01-478834
Busque, 2012, Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis, Nat Genet, 44, 1179, 10.1038/ng.2413
Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med, 20, 1472, 10.1038/nm.3733
Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med, 371, 2488, 10.1056/NEJMoa1408617
Li, 2011, Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies, Blood, 118, 4509, 10.1182/blood-2010-12-325241
Moran-Crusio, 2011, Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation, Cancer Cell, 20, 11, 10.1016/j.ccr.2011.06.001
Quivoron, 2011, TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis, Cancer Cell, 20, 25, 10.1016/j.ccr.2011.06.003
Zhao, 2015, Combined loss of Tet1 and Tet2 promotes B cell, but not myeloid malignancies, in mice, Cell Rep, 13, 1692, 10.1016/j.celrep.2015.10.037
He, 2011, Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA, Science, 333, 1303, 10.1126/science.1210944
Ito, 2011, Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine, Science, 333, 1300, 10.1126/science.1210597
Tahiliani, 2009, Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1, Science, 324, 930, 10.1126/science.1170116
Ko, 2010, Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2, Nature, 468, 839, 10.1038/nature09586
Nishikawa, 2015, DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway, Nat Med, 21, 281, 10.1038/nm.3774
Rhodes, 2015, Nf1 haploinsufficiency alters myeloid lineage commitment and function, leading to deranged skeletal homeostasis, J Bone Miner Res, 30, 1840, 10.1002/jbmr.2538
Zhao, 2016, The catalytic activity of TET2 is essential for its myeloid malignancy-suppressive function in hematopoietic stem/progenitor cells, Leukemia, 30, 1784, 10.1038/leu.2016.56
Lavin, 2014, Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment, Cell, 159, 1312, 10.1016/j.cell.2014.11.018
Song, 2011, Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine, Nat Biotechnol, 29, 68, 10.1038/nbt.1732
Huang, 2014, Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells, Proc Natl Acad Sci U S A, 111, 1361, 10.1073/pnas.1322921111
Pan, 2015, The TET2 interactors and their links to hematological malignancies, IUBMB Life, 67, 438, 10.1002/iub.1389
Pan, 2017, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, Nat Commun, 8, 15102, 10.1038/ncomms15102
Chen, 2013, TET2 promotes histone O-GlcNAcylation during gene transcription, Nature, 493, 561, 10.1038/nature11742
Deplus, 2013, TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS, EMBO J, 32, 645, 10.1038/emboj.2012.357
Vella, 2013, Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells, Mol Cell, 49, 645, 10.1016/j.molcel.2012.12.019
Guallar, 2018, RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells, Nat Genet, 50, 443, 10.1038/s41588-018-0060-9
Growney, 2005, Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative, Blood, 106, 494, 10.1182/blood-2004-08-3280
Soung do, 2014, Runx1-mediated regulation of osteoclast differentiation and function, Mol Endocrinol, 28, 546, 10.1210/me.2013-1305
Wilson, 2010, Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators, Cell Stem Cell, 7, 532, 10.1016/j.stem.2010.07.016
Lachmann, 2010, ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments, Bioinformatics, 26, 2438, 10.1093/bioinformatics/btq466
Yip, 2012, Classification of human genomic regions based on experimentally determined binding sites of more than 100 transcription-related factors, Genome Biol, 13, R48, 10.1186/gb-2012-13-9-r48
Ruocco, 2005, I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss, J Exp Med, 201, 1677, 10.1084/jem.20042081
Chen, 2013, C/EBPalpha regulates osteoclast lineage commitment, Proc Natl Acad Sci U S A, 110, 7294, 10.1073/pnas.1211383110
Suzuki, 2017, RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells, Blood Adv, 1, 1699, 10.1182/bloodadvances.2017005710
Wu, 2011, Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells, Nature, 473, 389, 10.1038/nature09934
Williams, 2011, TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity, Nature, 473, 343, 10.1038/nature10066
Pastor, 2011, Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells, Nature, 473, 394, 10.1038/nature10102
Ficz, 2011, Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation, Nature, 473, 398, 10.1038/nature10008
Zhang, 2015, Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6, Nature, 525, 389, 10.1038/nature15252
Montagner, 2016, TET2 regulates mast cell differentiation and proliferation through catalytic and non-catalytic activities, Cell Rep, 15, 1566, 10.1016/j.celrep.2016.04.044
Zhao, 2016, The catalytic activity of TET2 is essential for its myeloid malignancy-suppressive function in hematopoietic stem/progenitor cells, Leukemia, 30, 1784, 10.1038/leu.2016.56
Song, 2013, Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming, Cell, 153, 678, 10.1016/j.cell.2013.04.001
Lu, 2015, Base-resolution maps of 5-formylcytosine and 5-carboxylcytosine reveal genome-wide DNA demethylation dynamics, Cell Res, 25, 386, 10.1038/cr.2015.5
Wu, 2015, Charting oxidized methylcytosines at base resolution, Nat Struct Mol Biol, 22, 656, 10.1038/nsmb.3071
Camarena, 2017, cAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool, Elife, 6, e29750, 10.7554/eLife.29750
Trapnell, 2012, Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks, Nat Protoc, 7, 562, 10.1038/nprot.2012.016
Robinson, 2010, edgeR: a Bioconductor package for differential expression analysis of digital gene expression data, Bioinformatics, 26, 139, 10.1093/bioinformatics/btp616
Love, 2014, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol, 15, 550, 10.1186/s13059-014-0550-8
Zhang, 2008, Model-based analysis of ChIP-Seq (MACS), Genome Biol, 9, R137, 10.1186/gb-2008-9-9-r137
Machanick, 2011, MEME-ChIP: motif analysis of large DNA datasets, Bioinformatics, 27, 1696, 10.1093/bioinformatics/btr189