scholarly journals Effect of Disease-Associated Germline Mutations on Structure Function Relationship of DNA Methyltransferases

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 369 ◽  
Author(s):  
Allison B. Norvil ◽  
Debapriya Saha ◽  
Mohd Saleem Dar ◽  
Humaira Gowher
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Large Body ◽  
Genetic Alterations ◽  
Dna Methyltransferases ◽  
Neurological Dysfunction ◽  
Genome Association ◽  
Hereditary Disorders ◽  
Aberrant Dna Methylation ◽  
Function Relationship

Despite a large body of evidence supporting the role of aberrant DNA methylation in etiology of several human diseases, the fundamental mechanisms that regulate the activity of mammalian DNA methyltransferases (DNMTs) are not fully understood. Recent advances in whole genome association studies have helped identify mutations and genetic alterations of DNMTs in various diseases that have a potential to affect the biological function and activity of these enzymes. Several of these mutations are germline-transmitted and associated with a number of hereditary disorders, which are potentially caused by aberrant DNA methylation patterns in the regulatory compartments of the genome. These hereditary disorders usually cause neurological dysfunction, growth defects, and inherited cancers. Biochemical and biological characterization of DNMT variants can reveal the molecular mechanism of these enzymes and give insights on their specific functions. In this review, we introduce roles and regulation of DNA methylation and DNMTs. We discuss DNMT mutations that are associated with rare diseases, the characterized effects of these mutations on enzyme activity and provide insights on their potential effects based on the known crystal structure of these proteins.

scholarly journals Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications

2019 ◽  
Vol 20 (18) ◽  
pp. 4576 ◽  
Author(s):  
Xianwen Yang ◽  
Molly Pui Man Wong ◽  
Ray Kit Ng
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Epigenetic Modification ◽  
Critical Role ◽  
Genetic Alterations ◽  
Dna Methyltransferases ◽  
Clinical Implications ◽  
Aberrant Dna Methylation ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease that is characterized by distinct cytogenetic or genetic abnormalities. Recent discoveries in cancer epigenetics demonstrated a critical role of epigenetic dysregulation in AML pathogenesis. Unlike genetic alterations, the reversible nature of epigenetic modifications is therapeutically attractive in cancer therapy. DNA methylation is an epigenetic modification that regulates gene expression and plays a pivotal role in mammalian development including hematopoiesis. DNA methyltransferases (DNMTs) and Ten-eleven-translocation (TET) dioxygenases are responsible for the dynamics of DNA methylation. Genetic alterations of DNMTs or TETs disrupt normal hematopoiesis and subsequently result in hematological malignancies. Emerging evidence reveals that the dysregulation of DNA methylation is a key event for AML initiation and progression. Importantly, aberrant DNA methylation is regarded as a hallmark of AML, which is heralded as a powerful epigenetic marker in early diagnosis, prognostic prediction, and therapeutic decision-making. In this review, we summarize the current knowledge of DNA methylation in normal hematopoiesis and AML pathogenesis. We also discuss the clinical implications of DNA methylation and the current therapeutic strategies of targeting DNA methylation in AML therapy.

scholarly journals Neuroblastoma and the epigenome

2021 ◽  
Author(s):  
Irfete S. Fetahu ◽  
Sabine Taschner-Mandl
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Disease Diagnosis ◽  
Dna Methyltransferases ◽  
Epigenetic Alterations ◽  
Aberrant Expression ◽  
Tet Proteins ◽  
Relative Paucity ◽  
Underlying Causes ◽  
Aberrant Dna Methylation

AbstractNeuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system and one of the most common solid tumors in infancy. Amplification of MYCN, copy number alterations, numerical and segmental chromosomal aberrations, mutations, and rearrangements on a handful of genes, such as ALK, ATRX, TP53, RAS/MAPK pathway genes, and TERT, are attributed as underlying causes that give rise to NB. However, the heterogeneous nature of the disease—along with the relative paucity of recurrent somatic mutations—reinforces the need to understand the interplay of genetic factors and epigenetic alterations in the context of NB. Epigenetic mechanisms tightly control gene expression, embryogenesis, imprinting, chromosomal stability, and tumorigenesis, thereby playing a pivotal role in physio- and pathological settings. The main epigenetic alterations include aberrant DNA methylation, disrupted patterns of posttranslational histone modifications, alterations in chromatin composition and/or architecture, and aberrant expression of non-coding RNAs. DNA methylation and demethylation are mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, respectively, while histone modifications are coordinated by histone acetyltransferases and deacetylases (HATs, HDACs), and histone methyltransferases and demethylases (HMTs, HDMs). This article focuses predominately on the crosstalk between the epigenome and NB, and the implications it has on disease diagnosis and treatment.

scholarly journals DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas

2010 ◽  
Vol 207 (9) ◽  
pp. 1939-1950 ◽  
Author(s):  
Anne Y. Lai ◽  
Mehrnaz Fatemi ◽  
Archana Dhasarathy ◽  
Christine Malone ◽  
Steve E. Sobol ◽  
...  
Keyword(s):  
Dna Methylation ◽  
B Cell ◽  
Transcriptional Activation ◽  
Messenger Rna ◽  
Plasma Cells ◽  
Cpg Islands ◽  
Dna Methyltransferases ◽  
B Cell Lymphomas ◽  
Aberrant Dna Methylation ◽  
Bcl6 Expression

Aberrant DNA methylation commonly occurs in cancer cells where it has been implicated in the epigenetic silencing of tumor suppressor genes. Additional roles for DNA methylation, such as transcriptional activation, have been predicted but have yet to be clearly demonstrated. The BCL6 oncogene is implicated in the pathogenesis of germinal center–derived B cell lymphomas. We demonstrate that the intragenic CpG islands within the first intron of the human BCL6 locus were hypermethylated in lymphoma cells that expressed high amounts of BCL6 messenger RNA (mRNA). Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. These data indicate that BCL6 expression is maintained during lymphomagenesis in part through DNA methylation that prevents CTCF-mediated silencing.

scholarly journals Effect of 50 Hz Extremely Low-Frequency Electromagnetic Fields on the DNA Methylation and DNA Methyltransferases in Mouse Spermatocyte-Derived Cell Line GC-2

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Yong Liu ◽  
Wen-bin Liu ◽  
Kai-jun Liu ◽  
Lin Ao ◽  
Julia Li Zhong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Line ◽  
Biological Effects ◽  
Low Frequency ◽  
Dna Methyltransferases ◽  
Global Methylation ◽  
Genome Wide ◽  
Intermittent Exposure ◽  
Aberrant Dna Methylation

Previous studies have shown that the male reproductive system is one of the most sensitive organs to electromagnetic radiation. However, the biological effects and molecular mechanism are largely unclear. Our study was designed to elucidate the epigenetic effects of 50 Hz ELF-EMFin vitro. Mouse spermatocyte-derived GC-2 cell line was exposed to 50 Hz ELF-EMF (5 min on and 10 min off) at magnetic field intensity of 1 mT, 2 mT, and 3 mT with an intermittent exposure for 72 h. We found that 50 Hz ELF-EMF exposure decreased genome-wide methylation at 1 mT, but global methylation was higher at 3 mT compared with the controls. The expression of DNMT1 and DNMT3b was decreased at 1 mT, and 50 Hz ELF-EMF can increase the expression of DNMT1 and DNMT3b of GC-2 cells at 3 mT. However, 50 Hz ELF-EMF had little influence on the expression of DNMT3a. Then, we established DNA methylation and gene expression profiling and validated some genes with aberrant DNA methylation and expression at different intensity of 50 Hz ELF-EMF. These results suggest that the alterations of genome-wide methylation and DNMTs expression may play an important role in the biological effects of 50 Hz ELF-EMF exposure.

DNA methylation in breast cancer.

2001 ◽  
pp. 115-127 ◽  
Author(s):  
X Yang ◽  
L Yan ◽  
N E Davidson
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Tumor Suppressor ◽  
Breast Cancer Diagnosis ◽  
Genetic Alterations ◽  
Dna Methyltransferases ◽  
Imprinted Genes ◽  
Gene Transcriptional Regulation ◽  
Cancer Types

Like all cancers, breast cancer is considered to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. More recently, the role of epigenetic change as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes has emerged in many cancer types. This review will briefly discuss basic aspects of DNA methylation, recent advances in DNA methyltransferases, the role of altered chromatin organization and the concept of gene transcriptional regulation built on methylated CpGs. In particular, we discuss epigenetic regulation of certain critical tumor suppressor and growth regulatory genes implicated in breast cancer, and its relevance to breast cancer diagnosis, prognosis, progression and therapy.

ABERRANT DNA METHYLATION AS A CANCER-INDUCING MECHANISM

2005 ◽  
Vol 45 (1) ◽  
pp. 629-656 ◽  
Author(s):  
Manel Esteller
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Cpg Island ◽  
Gene Mutations ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Tumor Type ◽  
Suppressor Genes ◽  
Aberrant Dna Methylation

Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutations (nucleotide changes, deletions, recombinations) nor cytogenetic abnormalities are as common in human tumors as DNA methylation alterations. The most studied change of DNA methylation in neoplasms is the silencing of tumor suppressor genes by CpG island promoter hypermethylation, which targets genes such as p16INK4a, BRCA1, and hMLH1. There is a profile of CpG island hypermethylation according to the tumor type, and genes silent by methylation represent all cellular pathways. The introduction of bisulfite-PCR methodologies combined with new genomic approaches provides a comprehensive spectrum of the genes undergoing this epigenetic change across all malignancies. However, we still know very little about how this aberrant DNA methylation “invades” the previously unmethylated CpG island and how it is maintained through cell divisions. Furthermore, we should remember that this methylation occurs in the context of a global genomic loss of 5-methylcytosine (5mC). Initial clues to understand this paradox should be revealed from the current studies of DNA methyltransferases and methyl CpG binding proteins. From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively. Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high.

DNA Methyltransferase Inhibitors and their Therapeutic Potential

2019 ◽  
Vol 18 (28) ◽  
pp. 2448-2457 ◽  
Author(s):  
Zehao Zhou ◽  
Huan-Qiu Li ◽  
Feng Liu
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Dna Methyltransferases ◽  
Dna Methyltransferase Inhibitors ◽  
Dnmt Inhibitors ◽  
Aberrant Dna Methylation ◽  
Cancer Tissues ◽  
Nucleoside Inhibitors

Aberrant DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is associated with not only various cancers by silencing of tumor suppressor genes but also other diseases. The DNMTs, especially the DNMT1, DNMT3A and DNMT3B, are often overexpressed in various cancer tissues and cell lines. DNMTs are important epigenetic targets for drug development since the DNA methylation is reversible. This review summarizes an array of nucleoside and non-nucleoside inhibitors of DNMTs, as well as their biological activities. Among these inhibitors, the nucleoside analogue azacytidine and its deoxy derivative decitabine are both irreversible DNMT inhibitors and approved for the treatment of myelodysplastic syndrome.

Epigenetic events in the colorectum and in colon cancer

2005 ◽  
Vol 33 (4) ◽  
pp. 684-688 ◽  
Author(s):  
W.M. Grady
Keyword(s):  
Dna Methylation ◽  
Colon Cancer ◽  
Molecular Markers ◽  
Genetic Alterations ◽  
Epigenetic Mechanism ◽  
Field Cancerization ◽  
Aberrant Methylation ◽  
Colon Polyps ◽  
Aberrant Dna Methylation ◽  
Histological Progression

Colon cancers arise from benign neoplasms and evolve into adenocarcinomas through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations have been associated with specific steps in this polyp–adenocarcinoma sequence and are believed to drive the histological progression of colon cancer. Recently, epigenetic alterations, which include CGI (CpG island) DNA methylation, have been shown to occur in colon polyps and colon cancer. The aberrant methylation of genes appears to co-operate with the genetic alterations to drive the initiation and progression of colon polyps to colon cancer. CGI DNA methylation is an epigenetic mechanism that represses gene transcription in normal cellular processes, but it becomes excessive and aberrant in many neoplasms. The aberrant DNA methylation affects CpG-rich regions, called CGIs, in the 5′ region of genes and results in transcriptional silencing through effects on transcription factor binding and associated changes in chromatin structure. These hypermethylated genes are not only probable pathogenic events affecting colon-cancer formation, but also neoplasm-specific molecular events that may be useful as molecular markers for colon tumours. Furthermore, aberrant DNA methylation of tumour-suppressor genes may occur secondary to a genetic predisposition or to a field-cancerization effect in the colon and may be useful as molecular markers for the risk of developing colon cancer.

A Review of Aberrant DNA Methylation and Epigenetic Agents Targeting DNA Methyltransferases in Endometriosis

2020 ◽  
Vol 21 (11) ◽  
pp. 1047-1055
Author(s):  
Leilei Ding ◽  
Li Yang ◽  
Chenchen Ren ◽  
Huawen Zhang ◽  
Jie Lu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Therapeutic Approach ◽  
Essential Role ◽  
High Throughput Sequencing ◽  
Clinical Manifestations ◽  
Dna Methyltransferases ◽  
New Treatment ◽  
Aberrant Dna Methylation ◽  
Dna Methylation Inhibitors ◽  
Epigenetic Patterns

Background: Endometriosis (EMS) is a gynecological disease defined by the translocation and growth of endometrial tissue in other tissues or organs outside the uterus. Its clinical manifestations are dysmenorrhea, irregular menstruation, and even infertility. Although EMS is a benign disease, it has the characteristics of malignant tumor and the potential of malignant transformation. Recent studies have found that EMS may involve epigenetic changes and that various epigenetic aberrations, especially aberrant DNA methylation may play an essential role in the pathogenesis of EMS. Previous studies have elucidated the epigenetic regulators of EMS and reported variations in epigenetic patterns of genes known to be associated with abnormal hormonal, immune, and inflammatory states of EMS. With the development of high-throughput sequencing and other biomolecular technologies, we have a better understanding of genome-wide methylation in EMS. Objective: This article will discuss the potentiality of targeting DNA methylation as the therapeutic approach for EMS. Results: This article reviews the role of DNA methylation in the pathophysiology of EMS and provides insight into a novel therapeutic approach for EMS by targeting DNA methylation modifiers. We also review the current progress in using DNA methylation inhibitors in EMS therapy and the potential promise and challenges ahead. Conclusion: Aberrant DNA methylation plays an essential role in the pathogenesis of EMS and epigenetic agents targeting DNA methyltransferases are expected to be the theoretical basis for the new treatment of EMS.

scholarly journals Distinct blood DNA methylation profiles in subtypes of orofacial cleft

2017 ◽  
Author(s):  
Gemma C Sharp ◽  
Karen Ho ◽  
Amy Davies ◽  
Evie Stergiakouli ◽  
Kerry Humphries ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cleft Lip ◽  
Molecular Mechanisms ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Orofacial Cleft ◽  
Orofacial Clefts ◽  
Blood Samples ◽  
Aberrant Dna Methylation ◽  
Genomic Regions

AbstractBackgroundThere is evidence that different subtypes of orofacial cleft have distinct aetiologies, although the precise molecular mechanisms underlying these are unknown. Given the key role of epigenetic processes such as DNA methylation in embryonic development, it is likely that aberrant DNA methylation may also play a part in the development of orofacial clefts.MethodsIn this study, we explored whether blood samples from children with different cleft subtypes showed distinct DNA methylation profiles.In whole blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only CLO n=50; cleft palate only CPO n=50; cleft lip and palate CLP n=50).ResultsWe found four genomic regions differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. These regions included several mapping to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA) and over 250 novel associations.ConclusionOur finding of distinct methylation profiles in different cleft subtypes might reflect differences in their aetiologies, with DNA methylation either playing a causal role in development of OFC subtypes or reflecting causal genetic or environmental factors.

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