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Demethylating Agents in the Treatment of Cancer.

Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We als

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… Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation. Mol. Cancer Ther. 2009;8:225–231. doi: 10.1158/1535-7163.MCT-08-0743. 46. … Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc. Natl. Acad. Sci. USA. 1994;91:11797–11801. doi: 10.1073/pnas.91.25.11797. 58. Issa J.P., Kantarjian H.M. Targeting DNA methylation. Clin. …

Demethylation of promoter regulatory elements contributes to CD70 overexpression in CD4+ T cells from patients with subacute cutaneous lupus erythematosus.

BACKGROUND: Impaired methylation of T-cell DNA is thought to contribute to the development of systemic lupus erythematosus (SLE). CD70 (TNFSF7) is a B-cell costimulatory molecule that contributes to excessive B-cell stimulation in vitro and in vivo. CD70 is overexpressed in CD4+ T cells of patients with SLE, and DNA demethylation occurs in promoter sequences that regulate CD70 expression in SLE CD4+ T cells. However, it is unknown whether the expression and methylation of CD70 in CD4+ T cells are affected in patients with subacute cutaneous lupus erythematosus (SCLE). OBJECTIVE: To compare CD…

Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.

Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and f

Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU.

BACKGROUND: A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. RESULTS: We selected 36 early-PN and 36 late-PN matched patients, and 42 matched

Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome.

BACKGROUND: Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. RESULTS: We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS pa…

The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma.

Gene silencing by CpG island promoter hypermethylation has awakened the interest for DNA demethylating agents as chemotherapy drugs. Zebularine (1-[beta-D-ribofuranosil]-1,2-dihydropyrimidin-2-1) has been recently described as a new DNA methylation inhibitor. Here we have studied its effects in a mouse model of radiation-induced lymphomagenesis using nuclear magnetic resonance (NMR) and positron emission tomography (PET). All control animals presented large thymic T lymphomas and died between 4 and 5.5 months. In contrast, 40% (12 of 30) of zebularine-treated animals were still alive after 1 y

Reepithelialization of Diabetic Skin and Mucosal Wounds Is Rescued by Treatment With Epigenetic Inhibitors.

UNLABELLED: Wound healing is a complex, highly regulated process and is substantially disrupted by diabetes. We show here that human wound h … hat high glucose significantly increased FOXO1-matrix metallopeptidase 9 interactions via increased DNA demethylation, reduced DNA methylation, and increased permissive histone-3 methylation in vitro. Inhibitors of DNA demethylation and permissive histone-3 methylation improved the migration of keratinocytes exposed to high glucose in vitro and the closure of diabe …

Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome.

BACKGROUND: Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5-hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital. RESULTS: Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort o

Long-read sequencing reveals genomic and epigenomic variation in the dark genome of human Alzheimer's disease.

INTRODUCTION: Faulty DNA repair and epigenetic regulation contribute to neurodegeneration in Alzheimer's disease. Long-read sequencing enabl … insertions trended upward in late-stage disease. Enrichment of NAHR between repetitive regions and DNA demethylation were detected in early disease. Differential methylation of dark regions within specific Alzheimer's disease risk genes and repetitive elements occurred across disease stage. DISCUSSION: This study provides the first long-read analysis of repetitiv …

Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion.

UNLABELLED: PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with l…

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study.

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedaz … to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dos …

Epigenome editing-mediated restoration of FBN1 expression by demethylation of CpG island shore in porcine fibroblasts.

Fibrillin-1, an extracellular matrix protein encoded by the FBN1 gene, is crucial for maintaining connective tissue integrity. Mutations in … region. In this study, we employed epigenome editing using the dCas9-TET1 system to induce targeted DNA demethylation within the FBN1 CpG island shore, which became hypermethylated after a prolonged culture of porcine fetal fibroblast cells. This approach effectively reduced methylation in the targeted region, and cells expressing the dCas9-TET1 system maintained h …

Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.

The three mammalian TET dioxygenases oxidize the methyl group of 5-methylcytosine in DNA, and the oxidized methylcytosines are essential intermediates in all known pathways of DNA demethylation. To define the in vivo consequences of complete TET deficiency, we inducibly deleted all three Tet genes in the mouse genome. Tet1/2/3-inducible TKO (iTKO) mice succumbed to acute myeloid leukemia (AML) by 4 to 5 wk. Single-cell RNA sequencing of Tet iTKO bone marrow cells revealed the appearance of new myeloid cell populations characterized by a striking increase in expression of all members of the ste…

Epigenetics in inflammatory liver diseases: A clinical perspective (Review).

Inflammatory liver diseases are, nowadays, multifactorial and wide-spread, thus having an important socio-economic impact. Although the therapeutic algorithms are well-known in hepatitis, regardless of etiology, strategies to identify inflammatory hepatic lesions in early stages and to develop new epigenetic therapies should be prioritized. The main entities of inflammatory liver disease are: alcoholic and non-alcoholic fatty liver disease, autoimmune hepatitis, viral hepatitis and Wilson disease. The main epigenetic processes include: DNA methylation/demethylation, which imply changes in DNA

Testosterone Depletion Induces Demethylation of Murine Reelin Promoter CpG Dinucleotides: A Preliminary Study.

Schizophrenia (SZ) is a debilitating mental disorder characterized by psychotic events, abnormal social behavior, false beliefs, and auditory hallucinations. Hypermethylation of the promoter region of reelin (RELN), a gene involved in regulation of neuronal positioning during telencephalic development, is strongly associated with low protein expression in several cortical structures and promoter hypermethylation in brain from postmortem SZ subjects. Recent experimental data suggests that testosterone is able to promote RELN demethylation, although no direct evidence of hormonal influence on re

AZA-MS: a novel multiparameter mass spectrometry method to determine the intracellular dynamics of azacitidine therapy in vivo.

The cytidine analogue, 5-azacytidine (AZA; 5-AZA-cR), is the primary treatment for myelodysplastic syndrome and chronic myelomonocytic leuka … in the same sample using nanogram quantities of input material. We report that although AZA induces DNA demethylation in a dose-dependent manner, it has no corresponding effect on RNA methylation. By applying AZA-MS to primary bone marrow samples from patients undergoing AZA therapy, we have identified that responders accumulate more 5-AZA-CdR in their DNA compared …

Hypomethylation of pericentromeric DNA in breast adenocarcinomas.

Drug-induced DNA demethylation in normal human cells and inherited localized hypomethylation in mitogen-stimulated lymphocytes from patients with a rare recessive disease (ICF: immunodeficiency, centromeric region instability, facial anomalies) are associated with karyotypic instability. This chromosomal recombination is targeted to heterochromatin in the vicinity of the centromere (pericentromeric region) of human chromosome 1. Pericentromeric rearrangements in this chromosome as well as overall genomic hypomethylation are frequently observed in many kinds of cancer, including breast adenocar…

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

Sjögren's syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex … emethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers …

Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine.

Convincing evidence accumulated over the last decades demonstrates the crucial role of epigenetic modifications for mammalian genome regulat … lcytosine. 5hmC is a predominantly stable form and serves as both an intermediate product of active DNA demethylation and an essential hallmark of epigenetic gene regulation. This makes 5hmC a potential contributor to epigenetically mediated responses to environmental factors. In this state-of-the-art review, we consolidate the latest findings on environmentally in …

Genetic ablation of the TET family in retinal progenitor cells impairs photoreceptor development and leads to blindness.

The retina is responsible for converting light into electrical signals that, when transmitted to the brain, create the sensation of vision. The mammalian retina is epigenetically unique since the differentiation of retinal progenitor cells (RPCs) into retinal cells is accompanied by a decrease in DNA methylation in the promoters of many genes important for retinal development and function. However, the pathway responsible for DNA demethylation and its role in retinal development and function were unknown. We hypothesized that the Ten-Eleven Translocation (TET) family of dioxygenases plays a ke…