The classical model of cytosine DNA methylation (the presence of 5-methylcytosine, 5mC) regulation depicts this covalent modification as a stable repressive regulator of promoter activity. However, whole-genome analysis of 5mC reveals widespread tissue- and cell type–specific patterns and pervasive dynamics during mammalian development. Here we review recent findings that delineate 5mC functions in developmental stages and diverse genomic compartments as well as discuss the molecular mechanisms that connect transcriptional regulation and 5mC. Beyond the newly appreciated dynamics, regulatory roles for 5mC have been suggested in new biological contexts, such as learning and memory or aging. The use of new single-cell measurement techniques and precise editing tools will enable functional analyses of 5mC in gene expression, clarifying its role in various biological processes.

http://science.sciencemag.org/content/sci/361/6409/1336.full.pdf

Dynamic DNA methylation: In the right place at the right time

Maintenance of genome stability requires control over the expression of transposable elements (TEs), whose activity can have substantial deleterious effects on the host. Chemical modification of DNA is a commonly used strategy to achieve this, and it has long been argued that the emergence of 5-methylcytosine (5mC) in many species was driven by the requirement to silence TEs. Potential roles in TE regulation have also been suggested for other DNA modifications, such as N6-methyladenine and oxidation derivatives of 5mC, although the underlying mechanistic relationships are poorly understood. Here, we discuss current evidence implicating DNA modifications and DNA-modifying enzymes in TE regulation across different species.

/pdf/regulation-of-transposable-elements-by-dna-modifications-3bejp8ysu3.pdf

Regulation of transposable elements by DNA modifications

Chromatin is a macromolecular complex predominantly comprising DNA, histone proteins and RNA. The methylation of chromatin components is highly conserved as it helps coordinate the regulation of gene expression, DNA repair and DNA replication. Dynamic changes in chromatin methylation are essential for cell-fate determination and development. Consequently, inherited or acquired mutations in the major factors that regulate the methylation of DNA, RNA and/or histones are commonly observed in developmental disorders, ageing and cancer. This has provided the impetus for the clinical development of epigenetic therapies aimed at resetting the methylation imbalance observed in these disorders. In this Review, we discuss the cellular functions of chromatin methylation and focus on how this fundamental biological process is corrupted in cancer. We discuss methylation-based cancer therapies and provide a perspective on the emerging data from early-phase clinical trial therapies that target regulators of DNA and histone methylation. We also highlight promising therapeutic strategies, including monitoring chromatin methylation for diagnostic purposes and combination epigenetic therapy strategies that may improve immune surveillance in cancer and increase the efficacy of conventional and targeted anticancer drugs.

/pdf/the-roles-of-dna-rna-and-histone-methylation-in-ageing-and-1ixnnx1f5k.pdf

The roles of DNA, RNA and histone methylation in ageing and cancer.

N6-methyladenine DNA Modification in Glioblastoma

Molecular inputs to chromatin via cellular metabolism are modifiers of the epigenome. These inputs — which include both nutrient availability as a result of diet and growth factor signalling — are implicated in linking the environment to the maintenance of cellular homeostasis and cell identity. Recent studies have demonstrated that these inputs are much broader than had previously been known, encompassing metabolism from a wide variety of sources, including alcohol and microbiotal metabolism. These factors modify DNA and histones and exert specific effects on cell biology, systemic physiology and pathology. In this Review, we discuss the nature of these molecular networks, highlight their role in mediating cellular responses and explore their modifiability through dietary and pharmacological interventions. Various cellular metabolites provide the chemical moieties for DNA and histone modifications, resulting in a complex interplay between metabolism and epigenetics. In this Review, Dai, Ramesh and Locasale discuss the metabolic regulation of diverse types of chromatin modifications and the functional consequences of these modifications at the molecular, cellular and organismal levels, as well as influences from diet and microbiota.

The evolving metabolic landscape of chromatin biology and epigenetics.

N6-Methyladenine DNA Modification in the Human Genome.

In human cells, DNA 5-methylcytosine (5mC) modification plays an important role as an epigenetic mark. However, DNA N6-methyladenine modification (6mA), which is predominantly present in prokaryotes and a limited number of eukaryotes, is considered to be absent in human genomic DNA. Here, we show that 6mA is present in human genome, and we identified 881,240 6mA sites whose density is about 0.051% of the total adenines in the human genome DNA, but more than 0.18% in the mitochondrion genome. [G/C]AGG[C/T] was the most significant motif associated with 6mA modification. 6mA sites are enriched in the exon coding regions (P=0.02) and associated with transcriptional activation (P<0.001). We further identify that DNA N6-methyladenine and N6-demethyladenine modification is mediated by 6mA methytransferase N6AMT1 and 6mA demethytransferase ALKBH1, respectively. The 6mA abundance is significantly lower in cancer tissues compared to adjacent normal tissues, always accompanying with lower N6AMT1 and higher ALKBH1 level. Collectively, we uncover a DNA modification in human and describe a potential role of the N6AMT1/ALKBH1-6mA regulatory axis in the progression of human disease, such as cancer.

https://www.biorxiv.org/content/biorxiv/early/2018/03/18/176958.full.pdf

N6-Methyladenine DNA Modification in Human Genome

The invention provides application of an ALKBH1 gene and an expression product of the ALKBH1 gene in preparing a kit for diagnosing tumors and a drug for treating tumors. By detecting the expression situations of the ALKBH1 gene in tumor tissue of a patient suffering from stomach cancer or liver cancer, it is found that the expression level of the ALKBH1 gene is obviously improved. By building ALKBH1 gene over-expressed liver cancer and ovarian cancer cell strains to be compared with control groups respectively, the DNA6mA modification level, the multiplication capacity, the cell migration rate, the cell invasion capacity and the like of the ALKBH1 gene are obviously changed. The ALKBH1 gene and the expression product of the ALKBH1 gene are used as markers for diagnosing the tumors, so that the tumors are more accurately and quickly diagnosed; when the ALKBH1 gene and the expression product of the ALKBH1 gene are used as target genes for preparing drugs for treating the tumors, new therapeutic targets and therapy pathways are provided for treating the tumors.

Application of ALKBH1 gene and expression product of ALKBH1 gene in preparing kit for diagnosing tumors and drug for treating tumors

The invention provides applications of an N6AMT1 gene and an expression product thereof in preparing tumor diagnosis kits and tumor treatment medicines. According to the application, N6AMT1 gene expression situations in tumor tissue of patients suffering from stomach cancer and liver cancer are detected, and results show that the expression level of an N6AMT1 gene is remarkably reduced. Liver cancer and ovarian cancer cell strains with over-expressed/silenced N6AMT1 genes are established and are respectively compared with control groups, and results show that the DNA6mA modification level, themultiplication capacity, the cell migration rate, the cell invasion ability and the like of the genes are remarkably changed. Due to adoption of the N6AMT1 gene and the expression product thereof astumor diagnosis markers, tumor diagnosis can be carried out relatively accurately and rapidly, and as a target gene for preparing tumor treatment medicines, the gene provides novel treatment targets and treatment ways for tumor treatment.

He Minghui

Papers

N6-Methyladenine DNA Modification in the Human Genome.

N6-Methyladenine DNA Modification in Human Genome

Application of ALKBH1 gene and expression product of ALKBH1 gene in preparing kit for diagnosing tumors and drug for treating tumors

Applications of N6AMT1 gene and expression product thereof in preparing tumor diagnosis kits and tumor treatment medicines