Functions of TET Proteins in Hematopoietic Transformation

DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abnormal expression of oncogenes, tumor suppressor genes or repair genes. Ten-eleven-translocation (TET) proteins are recently characterized dioxygenases that catalyze progressive oxidation of 5-methylcytosine to produce 5-hydroxymethylcytosine and further oxidized derivatives. These oxidized methylcytosines not only potentiate DNA demethylation but also behave as independent epigenetic modifications per se. The expression or activity of TET proteins and DNA hydroxymethylation are highly dysregulated in a wide range of cancers including hematologic and non-hematologic malignancies, and accumulating evidence points TET proteins as a novel tumor suppressor in cancers. Here we review DNA demethylation-dependent and -independent functions of TET proteins. We also describe diverse TET loss-of-function mutations that are recurrently found in myeloid and lymphoid malignancies and their potential roles in hematopoietic transformation. We discuss consequences of the deficiency of individual Tet genes and potential compensation between different Tet members in mice. Possible mechanisms underlying facilitated oncogenic transformation of TET-deficient hematopoietic cells are also described. Lastly, we address non-mutational mechanisms that lead to suppression or inactivation of TET proteins in cancers. Strategies to restore normal 5mC oxidation status in cancers by targeting TET proteins may provide new avenues to expedite the development of promising anti-cancer agents.clos

Structural Health Monitoring

Abstract In structural health monitoring, crack identification using scattered ultrasonic waves from a crack is one of the most active research areas. Crack size estimation is important for judging the severity of the damage. If measurements are frequently performed as the crack grows, then a better estimation of crack size may be possible by analyzing sensor signals for the same crack location with different sizes. The objective of this article is to explore the relationship between the sensor signal amplitude and crack size through experiments and simulation for estimating the size. Cracks are machined into an aluminum plate and measurements are carried out with ultrasound excitation using piezoelectric transducer arrays that alternate their role as actuators or sensors. Initially, a hole of 2.5 mm diameter is drilled in the plate, and it is gradually machined to a crack with a size up to 50 mm. Signal amplitude is measured from the sensor arrays. The migration technique is used to image the crack and to find the crack location. The maximum received signal amplitude is found to vary linearly with size from simulation and this agrees with measurements with crack size up to 30 mm. The deviation between the simulation and experiment increases as the crack grows

Loss of adipose TET proteins enhances ??-adrenergic responses and protects against obesity by epigenetic regulation of ??3-AR expression

??-adrenergic receptor (??-AR) signaling plays predominant roles in modulating energy expenditure by triggering lipolysis and thermogenesis in adipose tissue, thereby conferring obesity resistance. Obesity is associated with diminished ??3-adrenergic receptor (??3-AR) expression and decreased ??-adrenergic responses, but the molecular mechanism coupling nutrient overload to catecholamine resistance remains poorly defined. Ten-eleven translocation (TET) proteins are dioxygenases that alter the methylation status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further oxidized derivatives. Here, we show that TET proteins are pivotal epigenetic suppressors of ??3-AR expression in adipocytes, thereby attenuating the responsiveness to ??-adrenergic stimulation. Deletion of all three Tet genes in adipocytes led to increased ??3-AR expression and thereby enhanced the downstream ??-adrenergic responses, including lipolysis, thermogenic gene induction, oxidative metabolism, and fat browning in vitro and in vivo. In mouse adipose tissues, Tet expression was elevated after mice ate a high-fat diet. Mice with adipose-specific ablation of all TET proteins maintained higher levels of ??3-AR in both white and brown adipose tissues and remained sensitive to ??-AR stimuli under high-fat diet challenge, leading to augmented energy expenditure and decreased fat accumulation. Consequently, they exhibited improved cold tolerance and were substantially protected from diet-induced obesity, inflammation, and metabolic complications, including insulin resistance and hyperlipidemia. Mechanistically, TET proteins directly repressed ??3-AR transcription, mainly in an enzymatic activity-independent manner, and involved the recruitment of histone deacetylases to increase deacetylation of its promoter. Thus, the TET-histone deacetylase-??3-AR axis could be targeted to treat obesity and related metabolic diseases

TET family dioxygenases and DNA demethylation in stem cells and cancers

The methylation of cytosine and subsequent oxidation constitutes a fundamental epigenetic modification in mammalian genomes, and its abnormalities are intimately coupled to various pathogenic processes including cancer development. Enzymes of the Ten-eleven translocation (TET) family catalyze the stepwise oxidation of 5-methylcytosine in DNA to 5-hydroxymethylcytosine and further oxidation products. These oxidized 5-methylcytosine derivatives represent intermediates in the reversal of cytosine methylation, and also serve as stable epigenetic modifications that exert distinctive regulatory roles. It is becoming increasingly obvious that TET proteins and their catalytic products are key regulators of embryonic development, stem cell functions and lineage specification. Over the past several years, the function of TET proteins as a barrier between normal and malignant states has been extensively investigated. Dysregulation of TET protein expression or function is commonly observed in a wide range of cancers. Notably, TET loss-of-function is causally related to the onset and progression of hematologic malignancy in vivo. In this review, we focus on recent advances in the mechanistic understanding of DNA methylation-demethylation dynamics, and their potential regulatory functions in cellular differentiation and oncogenic transformation

DNA methylation and hydroxymethylation in hematologic differentiation and transformation

Maintenance of balances of DNA methylation and demethylation plays fundamental roles in many biological processes. Aberrant DNA methylation-demethylation cycles is closely linked to the onset and progression of cancer. Proteins of the TET family are Fe(II)- and 2-oxoglutarate-dependent dioxygenases that catalyze iterative oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and subsequent oxidized derivatives. In addition to their roles as transient intermediate of DNA demethylation, these oxidized methylcytosines represent epigenetic marks that influence chromatin structure and gene expression. Loss of TET functions, which leads to marked disruption of DNA methylation and hydroxymethylation profiles, is commonly observed in a wide range of cancers. Particularly, TET loss-of-function is strongly associated with hematologic malignancies of lymphoid and myeloid origin as well as diverse solid cancers. In this talk, I will present our recent findings on the role of TET proteins in normal and malignant hematopoietic development, with an emphasis on the previously unappreciated functions of TET proteins in controlling genome-wide DNA methylation patterns, cell lineage commitment and genome integrity during hematopoiesis. Understanding of the impact of TET dysregulation during oncogenesis and identification of ways to manipulate TET activity in cancer cells may provide new avenues to develop novel epigenetic therapy applicable to a wide range of cancers

Editorial for the Special Issue “Molecular Mechanism of Leukemia”

Hematopoiesis is the intricate process responsible for all blood cell formation and maintenance, and is tightly regulated by a myriad of intrinsic and extrinsic factors [...

Epigenetic Modification of Cytosines in Hematopoietic Differentiation and Malignant Transformation

The mammalian DNA methylation landscape is established and maintained by the combined activities of the two key epigenetic modifiers, DNA methyltransferases (DNMT) and Ten-eleven-translocation (TET) enzymes. Once DNMTs produce 5-methylcytosine (5mC), TET proteins fine-tune the DNA methylation status by consecutively oxidizing 5mC to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives. The 5mC and oxidized methylcytosines are essential for the maintenance of cellular identity and function during differentiation. Cytosine modifications with DNMT and TET enzymes exert pleiotropic effects on various aspects of hematopoiesis, including self-renewal of hematopoietic stem/progenitor cells (HSPCs), lineage determination, differentiation, and function. Under pathological conditions, these enzymes are frequently dysregulated, leading to loss of function. In particular, the loss of DNMT3A and TET2 function is conspicuous in diverse hematological disorders, including myeloid and lymphoid malignancies, and causally related to clonal hematopoiesis and malignant transformation. Here, we update recent advances in understanding how the maintenance of DNA methylation homeostasis by DNMT and TET proteins influences normal hematopoiesis and malignant transformation, highlighting the potential impact of DNMT3A and TET2 dysregulation on clonal dominance and evolution of pre-leukemic stem cells to full-blown malignancies. Clarification of the normal and pathological functions of DNA-modifying epigenetic regulators will be crucial to future innovations in epigenetic therapies for treating hematological disorders

Functions of TET-mediated oxidation of 5-methylcytosine in hematologic cancer

Aberrant DNA methylation is a hallmark of cancer, and dysregulated DNA methylation-demethylation cycles is closely linked to the onset and progression of cancer. TET enzymes (TET1, TET2 and TET3) are Fe(II) and 2-ox- oglutarate-dependent dioxygenases that alter modification status of cytosines in DNA by successively oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Loss of TET functions and diminished genomic 5hmC levels are generally associated with oncogenic transformation in hematopoietic cancers as well as solid cancers. Particularly, TET2 gene is recurrently deleted or mutated in a wide spectrum of hematologic malignancies including myeloid and lymphoid malignancies. In this talk, I will present our recent findings on the role of TET proteins in normal and malignant hematopoietic development, with an em- phasis on the previously unappreciated functions of TET proteins in controlling cell lineage commitment and genome integrity during hematopoiesis. Together with the observations that TET proteins are key player of tumor growth and invasion, these studies suggest that manipulation of TET functions may provide new avenues to develop novel epigenetic therapies for treating cancers