Active DNA demethylation—The epigenetic gatekeeper of development, immunity, and cancer

Abstract

DNA methylation is a critical process in the regulation of gene expression with dramatic effects in development and continually expanding roles in oncogenesis. 5-Methylcytosine was once considered to be an inherited and stably repressive epigenetic mark, which can be only removed by passive dilution during multiple rounds of DNA replication. However, in the past two decades, physiologically controlled DNA demethylation and deamination processes have been identified, thereby revealing the function of cytosine methylation as a highly regulated and complex state-not simply a static, inherited signature or binary onoff switch. Alongside these fundamental discoveries, clinical studies over the past decade have revealed the dramatic consequences of aberrant DNA demethylation. In this review we discuss DNA demethylation and deamination in the context of 5-methylcytosine as critical processes for physiological and physiopathological transitions within three statesdevelopment, immune maturation, and oncogenic transformation; and we describe the expanding role of DNA demethylating drugs as therapeutic agents in cancer.

Functional significance of DNA methylation: epigenetic insights into Sjögren’s syndrome

“…Three mechanisms for demethylation have been identified: active demethylation (replication-independent), passive demethylation mediated by TET (replication-dependent), and 5mC deamination. In replication-independent active demethylation, TET dioxygenases oxidize 5mC to 5-hydroxymethylcytosine (5hmC), then to 5-formylcytosine (5fC), and finally to 5-carboxylcytosine (5caC) ( 20 ).…”

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis

“…Noteworthily, DNMT3A subcellular localization is not only nuclear, but has also been identified in the mitochondria where it may methylate mitochondrial DNA as well as in presynaptic MN terminals where its substrates and functions have not been identified yet [ 49 ]. If DNAm is a one-step process, demethylation instead requires multiple steps and involves several enzymatic players that are not all fully described, starting with an oxidation of the methyl residue by ten-eleven translocation enzymes (TETs) and leading to the formation of 5-hydroxymethylcytosine (5hmC, reviewed in [ 48 , 50 ]). While this contributes to view DNAm as the most stable and inheritable epigenetic mark, it should, however, be emphasized that DNAm is extremely dynamic with fast modulations occurring within the time frame of the circadian rhythm and slower modulations towards either hyper- or hypomethylation of CpG islands appearing over the entire lifespan (reviewed in [ 51 ]).…”

“…These long-term dynamics permitted the emergence of the so-called DNAm clocks, which can acutely assess the chronological age of individuals, and reflects the combination of genetics, epigenetics, and environmental factors within their biological age [ 52 ]. In all, DNAm is a fundamental gene expression regulatory element, associated with physiological and pathological developmental processes as well as physiological and pathological aging [ 48 , 50 , 52 ].…”

Can O-GIcNAc Transferase (OGT) Complex Be Used as a Target for the Treatment of Hematological Malignancies?

“…Numerous experimental and clinical data confirm that abnormalities in TET protein expression and function are closely associated with the development and progression of hematological malignancies [ 106 ]. The TET1 protein was first identified in patients with AML with chromosomal t (10; 11) (q22; q23) translocation, and TET1 is fused to the MLL gene [ 107 ]. Related studies have shown that TET1 binding to MLL leads to the upregulation of TET1 expression (overall increase in 5-hmC levels) and subsequent activation of signaling pathways such as Homeobox A (HOXA) 9, Meis homeobox 1 (Meis1), and pre-B-cell leukemia homeobox 3 (PBX3), which in turn promote the development and progression of MLL rearrangement leukemia [ 108 ].…”