Post-Translational Control of TET Function in Lymphoma

淋巴瘤 TET 功能的翻译后控制

• 批准号: 10512054
• 负责人: Ricardo C Aguiar
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512054
• 关键词: Acetyl Coenzyme A; Acetylation; Area; B-Cell Lymphomas; Balkans; Binding; Biology; Blood Cells; Cell Line; Chemical Exposure; DNA; DNA Methylation; Data; Development; Diagnosis; Distal; Early Diagnosis; Enhancers; Enzymes; Epigenetic Process; Exercise; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genomics; Glioma; Growth; Hexosamines; Histones; Human; Hyperactivity; In Vitro; Incidence; Infectious Agent; Leukemic Cell; Link; Location; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolism; Methylation; Military Personnel; Mitochondria; Mixed Function Oxygenases; Modeling; Mus; Myeloid Cells; Nature; Nuclear; O-GlcNAc transferase; Oncogenic; Organelles; Outcome; Output; Oxidoreductase; Pathology; Pathway interactions; Physiology; Play; Population; Post-Translational Protein Processing; Process; Proliferating; Reporter; Reporting; Research; Resolution; Risk; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Signal Transduction; Stem Cell Development; Testing; Tetanus Helper Peptide; Therapeutic; Tumor Suppressor Proteins; Veterans; Vietnam; Western World; Work; alpha ketoglutarate; base; cancer type; chromatin immunoprecipitation; defined contribution; demethylation; in vitro Model; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; mitochondrial metabolism; mouse model; novel; novel marker; oxidation; programs; promoter; segregation; stem cell biology; transcription factor; tumor

TET DNA hydroxylases are alpha-ketoglutarate (αKG)-dependent enzymes that catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), thus promoting DNA demethylation. Mapping of 5hmC marks at single base resolution demonstrated that the main role of TET enzymes is to maintain gene enhancers hypomethylated and active. Enhancers are genomic areas to which transcription factors bind to modulate gene expression programs. Hyperactive clusters of enhancers that are densely occupied by transcriptional factors are termed super- enhancers and are typically found in cancer. Like promoters, enhancers/super-enhancers are regulated by their DNA methylation status, a process that often goes awry in cancer. Thus, given that active enhancers and super- enhancers are oncogenic in nature, and that TET enzymes maintain them hypomethylated and active, we postulate that increased TET activity may itself be oncogenic. Mitochondria function as signaling organelles by generating substrates that fuel epigenetic changes, including for example acetylation and methylation of DNA and histones, respectively. Recently, we and others described a subtler interplay between mitochondria and epigenetics, wherein the levels of the intermediate metabolites αKG and 2-hydroxyglutarate were found to modulate the activity of TET enzymes, thus controlling DNA methylation. These findings led us to hypothesize that intermediary metabolism plays as an important role in the control of DNA methylation. Specifically, we posited that the mitochondrial enzymes D-2- and L-2-hydroxyglutarate dehydrogenase (D2HGDH and L2HGDH), which catalyze the interconversion of 2-HG to αKG, are integral to the cross talk between mitochondrial metabolism, TET function and super-enhancer demethylation/activation. To expand on this initial concept, we sought to identify upstream signals that regulate D2HGDH and L2HGDH expression and, consequently, influence TET function and enhancer methylation/activity. Using reporter and ChIP assays, inducible cell lines and mouse models, we recently reported that MYC transcriptionally activates D2HGDH and L2HGDH and, in a D2HGDH/L2HGDH/αKG-dependent manner, induces TET function leading to DNA demethylation in vitro and in vivo. Remarkably, we discovered that the MYC/D2-L2HGDH/αKG axis also promotes the nuclear accumulation of TET1, TET2 and TET3, in association with enhanced O-GlcNAcylation, a post-translational modification executed by another mitochondrial enzyme, O-GlcNAc transferase (OGT). Further, we preliminarily showed that in in diffuse large B cell lymphoma (DLBCL), MYC levels associated with enhancer methylation and target gene expression. Together, these data uncovered a novel mitochondrial signaling axis which includes MYC at the proximal point, D2/L2HGDH and OGT at the center, and, distally, TET activity and subcellular location. In this proposal, we will use human B cell lymphoma models in vitro and in vivo, to test the overarching hypothesis that intermediary metabolism, in part due to MYC activity, induces TET function, maintains oncogenic enhancers/super-enhancers hypomethylated and active and promote cancer. Our specific aims are: AIM 1) Determine the mechanistic basis for the increased O-GlcNAcylation mediated by the MYC-D2/L2HGDH-αKG axis and its role in promoting TET nuclear localization and enhancer activation. AIM 2) Define the contribution of the TET activation to MYC-driven lymphomagenesis AIM 3) Characterize the MYC- driven map of 5hmC marks and super-enhancer activation in B cell lymphoma. The proposed study is significant because it will define, and mechanistically elucidate, a novel role for MYC in cancer, i.e., activation of oncogenic enhancers/super-enhancers. Downstream to MYC, the contribution of D2HGDH-L2HGDH (via αKG generation) and O-GlucNAcylation will impart a post-translational control of TET function, which challenges the current dogma that these enzymes function exclusively as tumor suppressors.

TET DNA羟化酶是α -酮戊二酸（αKG）依赖性酶，催化5mC的氧化

项目成果

Cyclic-AMP signalling, MYC and hypoxia-inducible factor 1α intersect to regulate angiogenesis in B-cell lymphoma.

环磷酸腺苷信号传导、MYC 和缺氧诱导因子 1α 交叉调节 B 细胞淋巴瘤的血管生成。

• DOI: 10.1111/bjh.18196
• 发表时间: 2022
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Ethiraj,Purushoth;Sasi,Binu;Holder,KennethN;Lin,An-Ping;Qiu,Zhijun;Jaafar,Carine;Elkhalili,Alia;Desai,Parth;Saksena,Annapurna;Ritter,JacobP;Aguiar,RicardoCT
• 通讯作者: Aguiar,RicardoCT

MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.

• DOI: 10.1038/s41375-021-01489-7
• 发表时间: 2022-04
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Lin AP;Qiu Z;Ethiraj P;Sasi B;Jaafar C;Rakheja D;Aguiar RCT
• 通讯作者: Aguiar RCT