The DNA methyltransferase family: a versatile toolkit for epigenetic regulation

Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. Although only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post‐translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging‐related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short noncoding RNAs, and post‐translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. Environ. Mol. Mutagen., 60:668–682, 2019. © 2019 Wiley Periodicals, Inc.

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“…2; reviewed in Jin and Robertson, 2013;Lyko, 2018). 2; reviewed in Jin and Robertson, 2013;Lyko, 2018).…”

Section: The Enigma Of Mtdna Methylationmentioning

confidence: 99%

Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

128

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“…The DNMT family of proteins, which includes DNMT1, DNMT3A, and DNMT3B, are mainly involved in the mediation of CpG island methylation [32], whereas the HDAC family regulates histone deacetylation [33]. Consequently, a complex which includes MBD2, MECP1, and HDACs was formed via the DNA methylation, histone deacetylation and the methylation-dependent binding of MECP2 [34, 35].…”

Section: Discussionmentioning

confidence: 99%

The Long Noncoding RNA MEG3 and its Target miR-147 Regulate JAK/STAT Pathway in Advanced Chronic Myeloid Leukemia

Yang

Liu

et al. 2018

EBioMedicine

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BackgroundLong non-coding (lnc) RNAs plays an important role in chronic myeloid leukemia (CML). In this study, we aimed to uncover the mechanism of the lncRNA maternally expressed 3 (MEG3) and its target microRNA-147 (miR-147) in CML.MethodsSixty CML patients and 10 healthy donors were included in the study. The methylation of MEG3 and miR-147 promoter was determined by methylation-specific PCR. The relationship of MEG3 and miR-147 was explored by luciferase assay. The interactions of proteins were studied by RNA pull-down assay, RNA immunoprecipitation and co-immunoprecipitation.FindingsPatients in accelerated phase CML (CML-AP) and blast phase CML (CML-BP) showed lower expressions of MEG3 and miR-147 and higher expressions of DNMT1, DNMT3B, MBD2, MECP2 and HDAC1 compared to the controls. These patients also showed a higher degree of methylation of MEG3 and miR-147 while there was a reduction after chidamide treatment. Furthermore, the overexpression of MEG3 and miR-147 inhibited cell proliferation both in vivo and in vitro, promoted apoptosis and decreased the expressions of DNMT1, DNMT3A, DNMT3B, MBD2, HDAC1 and MECP2. We also found MEG3 interacted with DNMT1, JAK2, STAT3, HDAC1, and TYK2, and JAK2 was bound to STAT3, STAT5 and MYC. More interestingly, JAK2 was bound to TYK2 by the bridge of MEG3.InterpretationLncRNA MEG3 and its target miR-147 may serve as a novel therapeutic target for CML blast crisis, and chidamide might have a potential clinical application in treating CML blast crisis.

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“…DNA methylation is one type of epigenetic modification present in diverse taxa and is involved in the control of gene regulation, normally associated with transcriptional silencing. DNA methyltransferases ( Dnmt ) are a family of enzymes that catalyse the transfer of methyl groups to the genome template to maintain the pattern of methylation (imprinting control) or to modify the methylation pattern de novo. It has recently emerged that de novo DNA methylation is reversible and can exhibit clear oscillations in post‐mitotic cells .…”

Section: Introductionmentioning

confidence: 99%

Ovarian hormones induce de novo DNA methyltransferase expression in the Siberian hamster suprachiasmatic nucleus

Coyle

Caso

Tolla

et al. 2020

J Neuroendocrinology

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The present study investigated neuroanatomically localised changes in de novo DNA methyltransferase expression in the female Siberian hamster (Phodopus sungorus). The objectives were to identify the neuroendocrine substrates that exhibit rhythmic Dnmt3a and Dnmt3b expression across the oestrous cycle and also examine the role of ovarian steroids. Hypothalamic Dnmt3a expression was observed to significantly increase during the transition from pro‐oestrous to oestrous. A single bolus injection of diethylstilbestrol and progesterone was sufficient to increase Dnmt3a cell numbers and Dnmt3b immunoreactive intensity in the suprachiasmatic nucleus. In vitro analyses using an embryonic rodent cell line revealed that diethylstilbestrol was sufficient to induce Dnmt3b expression. Up‐regulating DNA methylation in vitro reduced the expression of vasoactive intestinal polypeptide, Vip, and the circadian clock gene, Bmal1. Together, these data indicate that ovarian steroids drive de novo DNA methyltransferase expression in the mammalian suprachiasmatic nucleus and increased methylation may regulate genes involved in the circadian timing of oestrous: Vip and Bmal1. Overall, epigenetically mediated neuroendocrine reproductive events may reflect an evolutionarily ancient process involved in the timing of female fertility.

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The DNA methyltransferase family: a versatile toolkit for epigenetic regulation

Cited by 1,075 publications

References 156 publications

Mitochondrial DNA: Epigenetics and environment

Mitochondrial DNA: Epigenetics and environment

The Long Noncoding RNA MEG3 and its Target miR-147 Regulate JAK/STAT Pathway in Advanced Chronic Myeloid Leukemia

Ovarian hormones induce de novo DNA methyltransferase expression in the Siberian hamster suprachiasmatic nucleus

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