The TET enzymes

Koivunen, Peppi; Laukka, Tuomas

doi:10.1007/s00018-017-2721-8

Cited by 61 publications

(58 citation statements)

References 92 publications

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“…Epigenetic modifications of the nucleic acid and protein components of chromatin are central regulators of eukaryotic transcription. These modifications include the reversible methylation of DNA and histones and further histone modifications such as acetylation, phosphorylation and ubiquitination 1 The chromatin modifications are written or erased by enzymes, with several of the erasers belonging to the family of 2oxoglutarate-dependent dioxygenases (2-OGDDs) [1][2][3][4] . The family contains ~70 enzymes in humans, including a large number of histone lysine demethylases (KDMs), the DNA demethylases, ten-eleven translocation (TET) enzymes, the hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also known as EglNs and PHDs) and several enzymes required for collagen biosynthesis 1,2,4 .…”

Section: Introductionmentioning

confidence: 99%

Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases

Laukka

Myllykoski

Looper

et al. 2018

Journal of Molecular Biology

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Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. Their dysregulation has been associated with many cancers. We set out to study the catalytic and inhibitory properties of human KDM4A, KDM4B, KDM5B, KDM6A and KDM6B, aiming in particular to reveal which of these enzymes are targeted by cancer-associated 2-oxoglutarate (2-OG) analogues. We used affinity-purified insect cell-produced enzymes and synthetic peptides with trimethylated lysines as substrates for the in vitro enzyme activity assays. In addition, we treated breast cancer cell lines with cell-permeable forms of 2-OG analogues and studied their effects on the global histone methylation state. Our data show that KDMs have substrate specificity. Among the enzymes studied, KDM5B had the highest affinity for the peptide substrate but the lowest affinity for the 2-OG and the Fe cosubstrate/cofactors. R-2-hydroxyglutarate (R-2HG) was the most efficient inhibitor of KDM6A, KDM4A and KDM4B, followed by S-2HG. This finding was supported by accumulations of the histone H3K9me3 and H3K27me3 marks in cells treated with the cell-permeable forms of these compounds. KDM5B was especially resistant to inhibition by R-2HG, while citrate was the most efficient inhibitor of KDM6B. We conclude that KDM catalytic activity is susceptible to inhibition by tumorigenic 2-OG analogues and suggest that the inhibition of KDMs is involved in the disease mechanism of cancers in which these compounds accumulate, such as the isocitrate dehydrogenase mutations.

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Section: Introductionmentioning

confidence: 99%

Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases

Laukka

Myllykoski

Looper

et al. 2018

Journal of Molecular Biology

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“…An obvious context in which 5hmC occupancy is expected to be dysregulated is malignant disease (specialized reviews on cancer and TET-dependent 5hmC have been recently published [114][115][116][117][118]). Indeed, while Tet deletions/mutations have been shown to predispose to blood malignancies, cancer was initially associated with a global loss of 5hmC in various tissues [65,66].…”

Section: Perspectives and Concluding Remarksmentioning

confidence: 99%

5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell

2018

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Abstract:Recently described as the sixth base of the DNA macromolecule, the precise role of 5-hydroxymethylcytosine (5hmC) is the subject of debate. Early studies indicate that it is functionally distinct from cytosine DNA methylation (5mC), and there is evidence for 5hmC being a stable derivate of 5mC, rather than just an intermediate of demethylation. Moreover, 5hmC events correlate in time and space with key differentiation steps in mammalian cells. Such events span the three embryonic germ layers and multiple progenitor cell subtypes, suggesting a general mechanism. Because of the growing understanding of the role of progenitor cells in disease origin, we attempted to provide a detailed summary on the currently available literature supporting 5hmC as a key player in adult progenitor cell differentiation. This summary consolidates the emerging role for 5hmC in defining cellular fate.

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“…DNA demethylation involves the TET family of methylcytosine dioxygenases that are α-KG-dependent enzymes (Koivunen and Laukka, 2018). This family consists of TET1, TET2, and TET3, which participate in the conversion of 5-mC to 5-hmC to promote reversal of methylation (Ito et al, 2010;Melamed et al, 2018).…”

Section: Ten-eleven Translocationmentioning

confidence: 99%

Epigenetic Regulation of Excitatory Amino Acid Transporter 2 in Neurological Disorders

Alam

Datta

2019

Front. Pharmacol.

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Excitatory amino acid transporter 2 (EAAT2) is the predominant astrocyte glutamate transporter involved in the reuptake of the majority of the synaptic glutamate in the mammalian central nervous system (CNS). Gene expression can be altered without changing DNA sequences through epigenetic mechanisms. Mechanisms of epigenetic regulation, include DNA methylation, post-translational modifications of histones, chromatin remodeling, and small non-coding RNAs. This review is focused on neurological disorders, such as glioblastoma multiforme (GBM), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), bipolar disorder (BD), and neuroHIV where there is evidence that epigenetics plays a role in the reduction of EAAT2 expression. The emerging field of pharmaco-epigenetics provides a novel avenue for epigenetics-based drug therapy. This review highlights findings on the role of epigenetics in the regulation of EAAT2 in different neurological disorders and discusses the current pharmacological approaches used and the potential use of novel therapeutic approaches to induce EAAT2 expression in neurological disorders using CRISPR/Cas9 technology.

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The TET enzymes

Cited by 61 publications

References 92 publications

Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases

Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases

5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell

Epigenetic Regulation of Excitatory Amino Acid Transporter 2 in Neurological Disorders

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