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Clinical Epigenetics Apr 2021In DNA methylation analyses like epigenome-wide association studies, effects in differentially methylated CpG sites are assessed. Two kinds of outcomes can be used for...
BACKGROUND
In DNA methylation analyses like epigenome-wide association studies, effects in differentially methylated CpG sites are assessed. Two kinds of outcomes can be used for statistical analysis: Beta-values and M-values. M-values follow a normal distribution and help to detect differentially methylated CpG sites. As biological effect measures, differences of M-values are more or less meaningless. Beta-values are of more interest since they can be interpreted directly as differences in percentage of DNA methylation at a given CpG site, but they have poor statistical properties. Different frameworks are proposed for reporting estimands in DNA methylation analysis, relying on Beta-values, M-values, or both.
RESULTS
We present and discuss four possible approaches of achieving estimands in DNA methylation analysis. In addition, we present the usage of M-values or Beta-values in the context of bioinformatical pipelines, which often demand a predefined outcome. We show the dependencies between the differences in M-values to differences in Beta-values in two data simulations: a analysis with and without confounder effect. Without present confounder effects, M-values can be used for the statistical analysis and Beta-values statistics for the reporting. If confounder effects exist, we demonstrate the deviations and correct the effects by the intercept method. Finally, we demonstrate the theoretical problem on two large human genome-wide DNA methylation datasets to verify the results.
CONCLUSIONS
The usage of M-values in the analysis of DNA methylation data will produce effect estimates, which cannot be biologically interpreted. The parallel usage of Beta-value statistics ignores possible confounder effects and can therefore not be recommended. Hence, if the differences in Beta-values are the focus of the study, the intercept method is recommendable. Hyper- or hypomethylated CpG sites must then be carefully evaluated. If an exploratory analysis of possible CpG sites is the aim of the study, M-values can be used for inference.
Topics: DNA Methylation; Epigenesis, Genetic; Epigenome; Genome-Wide Association Study; Humans
PubMed: 33926513
DOI: 10.1186/s13148-021-01083-9 -
Critical Reviews in Biochemistry and... 2016Over the past decade, since epigenetic mechanisms were first implicated in memory formation and synaptic plasticity, dynamic DNA methylation reactions have been... (Review)
Review
Over the past decade, since epigenetic mechanisms were first implicated in memory formation and synaptic plasticity, dynamic DNA methylation reactions have been identified as integral to long-term memory formation, maintenance, and recall. This review incorporates various new findings that DNA methylation mechanisms are important regulators of non-Hebbian plasticity mechanisms, suggesting that these epigenetic mechanisms are a fundamental link between synaptic plasticity and metaplasticity. Because the field of neuroepigenetics is so young and the biochemical tools necessary to probe gene-specific questions are just now being developed and used, this review also speculates about the direction and potential of therapeutics that target epigenetic mechanisms in the central nervous system and the unique pharmacokinetic and pharmacodynamic properties that epigenetic therapies may possess. Mapping the dynamics of the epigenome in response to experiential learning, even a single epigenetic mark in isolation, remains a significant technical and bioinformatic hurdle facing the field, but will be necessary to identify changes to the methylome that govern memory-associated gene expression and effectively drug the epigenome.
Topics: Animals; DNA Methylation; Drug Discovery; Epigenesis, Genetic; Genomics; Humans; Memory; Neuronal Plasticity
PubMed: 26915423
DOI: 10.3109/10409238.2016.1150958 -
Clinical Epigenetics Oct 2021Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in... (Review)
Review
Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in multiple cellular processes. As a conserved histone methylation mark, histone 3 lysine 36 trimethylation (H3K36me3) can mediate multiple transcriptional-related events, such as the regulation of transcriptional activity, transcription elongation, pre-mRNA alternative splicing, and RNA mA methylation. Additionally, H3K36me3 also contributes to DNA damage repair. Given the crucial function of H3K36me3 in genome regulation, the roles of H3K36me3 and its sole methyltransferase SETD2 in pathogenesis, especially malignancies, have been emphasized in many studies, and it is conceivable that disruption of histone methylation regulatory network composed of "writer", "eraser", "reader", and the mutation of H3K36me3 codes have the capacity of powerfully modulating cancer initiation and development. Here we review H3K36me3-mediated biological processes and summarize the latest findings regarding its role in cancers. We highlight the significance of epigenetic combination therapies in cancers.
Topics: DNA Methylation; Epigenesis, Genetic; Histones; Humans; Neoplasms
PubMed: 34715919
DOI: 10.1186/s13148-021-01187-2 -
Cells Oct 2019DNA methylation controls several cellular processes, from early development to old age, including biological responses to endogenous or exogenous stimuli contributing to... (Review)
Review
DNA methylation controls several cellular processes, from early development to old age, including biological responses to endogenous or exogenous stimuli contributing to disease transition. As a result, minimal DNA methylation changes during developmental stages drive severe phenotypes, as observed in germ-line imprinting disorders, while genome-wide alterations occurring in somatic cells are linked to cancer onset and progression. By summarizing the molecular events governing DNA methylation, we focus on the methods that have facilitated mapping and understanding of this epigenetic mark in healthy conditions and diseases. Overall, we review the bright (health-related) and dark (disease-related) side of DNA methylation changes, outlining how bulk and single-cell genomic analyses are moving toward the identification of new molecular targets and driving the development of more specific and less toxic demethylating agents.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genome; Genomic Imprinting; Humans; Neoplasms
PubMed: 31614870
DOI: 10.3390/cells8101243 -
Oncotarget Oct 2015
Topics: 5-Methylcytosine; Cytosine; DNA Methylation; DNA Repair; Humans
PubMed: 26461852
DOI: 10.18632/oncotarget.6039 -
Plant Physiology Aug 2015DNA methylation within transcribed genes is commonly found in diverse animals and plants. Here, we provide an overview of recent advances and the remaining mystery... (Review)
Review
DNA methylation within transcribed genes is commonly found in diverse animals and plants. Here, we provide an overview of recent advances and the remaining mystery regarding intragenic DNA methylation.
Topics: DNA Methylation; DNA, Intergenic; DNA, Plant; Plants
PubMed: 26143255
DOI: 10.1104/pp.15.00543 -
International Journal of Molecular... May 2017Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile... (Review)
Review
Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including , , , (), and are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for the diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors holds considerable promise for the treatment of cholangiocarcinoma through the reactivation of tumor suppressor genes and miRNAs as well as the induction of an anti-viral immune response.
Topics: Animals; Biomarkers, Tumor; Cholangiocarcinoma; DNA Methylation; Gene Expression Regulation, Neoplastic; Humans
PubMed: 28545228
DOI: 10.3390/ijms18061111 -
Genome Biology Dec 2016Despite major progress in dissecting the molecular pathways that control DNA methylation patterns in plants, little is known about the mechanisms that shape plant... (Review)
Review
Despite major progress in dissecting the molecular pathways that control DNA methylation patterns in plants, little is known about the mechanisms that shape plant methylomes over evolutionary time. Drawing on recent intra- and interspecific epigenomic studies, we show that methylome evolution over long timescales is largely a byproduct of genomic changes. By contrast, methylome evolution over short timescales appears to be driven mainly by spontaneous epimutational events. We argue that novel methods based on analyses of the methylation site frequency spectrum (mSFS) of natural populations can provide deeper insights into the evolutionary forces that act at each timescale.
Topics: Arabidopsis; DNA Methylation; Evolution, Molecular; Gene Expression Regulation, Plant; Genetic Variation; Genome, Plant
PubMed: 27998290
DOI: 10.1186/s13059-016-1127-5 -
The New Phytologist Jul 2020DNA methylation is an epigenetic mark that regulates multiple processes, such as gene expression and genome stability. Mutants and pharmacological treatments have been... (Review)
Review
DNA methylation is an epigenetic mark that regulates multiple processes, such as gene expression and genome stability. Mutants and pharmacological treatments have been instrumental in the study of this mark in plants, although their genome-wide effect complicates the direct association between changes in methylation and a particular phenotype. A variety of tools that allow locus-specific manipulation of DNA methylation can be used to assess its direct role in specific processes, as well as to create novel epialleles. Recently, new tools that recruit the methylation machinery directly to target loci through programmable DNA-binding proteins have expanded the tool kit available to researchers. This review provides an overview of DNA methylation in plants and discusses the tools that have recently been developed for its manipulation.
Topics: DNA Methylation; Plants
PubMed: 32159848
DOI: 10.1111/nph.16529 -
Nucleic Acids Research Aug 2023Integrative analysis of multi-omic datasets has proven to be extremely valuable in cancer research and precision medicine. However, obtaining multimodal data from the...
Integrative analysis of multi-omic datasets has proven to be extremely valuable in cancer research and precision medicine. However, obtaining multimodal data from the same samples is often difficult. Integrating multiple datasets of different omics remains a challenge, with only a few available algorithms developed to solve it. Here, we present INTEND (IntegratioN of Transcriptomic and EpigeNomic Data), a novel algorithm for integrating gene expression and DNA methylation datasets covering disjoint sets of samples. To enable integration, INTEND learns a predictive model between the two omics by training on multi-omic data measured on the same set of samples. In comprehensive testing on 11 TCGA (The Cancer Genome Atlas) cancer datasets spanning 4329 patients, INTEND achieves significantly superior results compared with four state-of-the-art integration algorithms. We also demonstrate INTEND's ability to uncover connections between DNA methylation and the regulation of gene expression in the joint analysis of two lung adenocarcinoma single-omic datasets from different sources. INTEND's data-driven approach makes it a valuable multi-omic data integration tool. The code for INTEND is available at https://github.com/Shamir-Lab/INTEND.
Topics: Humans; DNA Methylation; Neoplasms; Algorithms; Gene Expression Profiling; Transcriptome
PubMed: 37395437
DOI: 10.1093/nar/gkad566