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Life Science Alliance Dec 2023Current methods for profiling DNA methylation require costly reagents, sequencing, and labor time. We introduce fragmentation at methylated loci and sequencing...
Current methods for profiling DNA methylation require costly reagents, sequencing, and labor time. We introduce fragmentation at methylated loci and sequencing (FML-seq), a sequencing library protocol that greatly reduces all these costs. Relative to other techniques tested on the same human cell lines, FML-seq produces similar measurements of absolute and differential cytosine methylation at a fraction of the price. FML-seq enables inexpensive, high-throughput experimental designs for large-scale epigenetics research projects.
Topics: Humans; DNA Methylation; Fluorometholone; CpG Islands; Cost-Benefit Analysis; Epigenesis, Genetic
PubMed: 37775270
DOI: 10.26508/lsa.202302326 -
Cells Aug 2019Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as... (Review)
Review
Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as much as 1% of the population worldwide. To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood. The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients' functional capacity and their quality of life. As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS-fibroblast-like synoviocytes) activity when it is necessary. It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results. Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable "liquid biopsy", thus providing a reliable template for assessing molecular markers of various diseases, including RA. Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA. In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.
Topics: Animals; Arthritis, Rheumatoid; DNA Methylation; Humans
PubMed: 31443448
DOI: 10.3390/cells8090953 -
Essays in Biochemistry Oct 2020Cells encounter a multitude of external and internal stress-causing agents that can ultimately lead to DNA damage, mutations and disease. A cascade of signaling events... (Review)
Review
Cells encounter a multitude of external and internal stress-causing agents that can ultimately lead to DNA damage, mutations and disease. A cascade of signaling events counters these challenges to DNA, which is termed as the DNA damage response (DDR). The DDR preserves genome integrity by engaging appropriate repair pathways, while also coordinating cell cycle and/or apoptotic responses. Although many of the protein components in the DDR are identified, how chemical modifications to DNA impact the DDR is poorly understood. This review focuses on our current understanding of DNA methylation in maintaining genome integrity in mammalian cells. DNA methylation is a reversible epigenetic mark, which has been implicated in DNA damage signaling, repair and replication. Sites of DNA methylation can trigger mutations, which are drivers of human diseases including cancer. Indeed, alterations in DNA methylation are associated with increased susceptibility to tumorigenesis but whether this occurs through effects on the DDR, transcriptional responses or both is not entirely clear. Here, we also highlight epigenetic drugs currently in use as therapeutics that target DNA methylation pathways and discuss their effects in the context of the DDR. Finally, we pose unanswered questions regarding the interplay between DNA methylation, transcription and the DDR, positing the potential coordinated efforts of these pathways in genome integrity. While the impact of DNA methylation on gene regulation is widely understood, how this modification contributes to genome instability and mutations, either directly or indirectly, and the potential therapeutic opportunities in targeting DNA methylation pathways in cancer remain active areas of investigation.
Topics: Animals; DNA Methylation; Genome; Humans
PubMed: 32808652
DOI: 10.1042/EBC20200009 -
Current Opinion in Psychology Jun 2019The recent interest in epigenetics within mental health research, from a developmental perspective, stems from the potential of DNA methylation to index both exposure to... (Review)
Review
The recent interest in epigenetics within mental health research, from a developmental perspective, stems from the potential of DNA methylation to index both exposure to adversity and vulnerability for mental health problems. Genome-wide technology has facilitated epigenome-wide association studies (EWAS), permitting 'hypothesis-free' examinations in relation to adversity and/or mental health problems. In EWAS, rather than focusing on a priori established candidate genes, the genome is screened for DNA methylation, thereby enabling a more comprehensive representation of variation associated with complex disease. Despite their 'hypothesis-free' label, however, results of EWAS are in fact conditional on several a priori hypotheses, dictated by the design of EWAS platforms as well as assumptions regarding the relevance of the biological tissue for mental health phenotypes. In this short report, we review three hidden hypotheses - and provide recommendations - that combined will be useful in designing and interpreting EWAS projects.
Topics: DNA Methylation; Epigenomics; Genome-Wide Association Study; Humans; Mental Disorders; Phenotype
PubMed: 30077874
DOI: 10.1016/j.copsyc.2018.07.009 -
Essays in Biochemistry Dec 2019Dynamic binding of transcription factors (TFs) to regulatory elements controls transcriptional states throughout organism development. Epigenetics modifications, such as... (Review)
Review
Dynamic binding of transcription factors (TFs) to regulatory elements controls transcriptional states throughout organism development. Epigenetics modifications, such as DNA methylation mostly within cytosine-guanine dinucleotides (CpGs), have the potential to modulate TF binding to DNA. Although DNA methylation has long been thought to repress TF binding, a more recent model proposes that TF binding can also inhibit DNA methylation. Here, we review the possible scenarios by which DNA methylation and TF binding affect each other. Further in vivo experiments will be required to generalize these models.
Topics: Animals; DNA; DNA Methylation; Epigenesis, Genetic; Humans; Protein Binding; Transcription Factors
PubMed: 31755929
DOI: 10.1042/EBC20190033 -
Journal of Neurochemistry May 2016Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory... (Review)
Review
Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. However, circuit development and stabilization additionally relies on non-Hebbian, homeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell-wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and demethylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.
Topics: Animals; DNA Methylation; Humans; Memory; Neuronal Plasticity; Receptors, Glutamate; Synapses
PubMed: 26849493
DOI: 10.1111/jnc.13564 -
Trends in Endocrinology and Metabolism:... Jan 2017In contrast to white adipose tissue (WAT), which stores energy in the form of triglycerides, brown adipose tissue (BAT) dissipates energy by producing heat to maintain... (Review)
Review
In contrast to white adipose tissue (WAT), which stores energy in the form of triglycerides, brown adipose tissue (BAT) dissipates energy by producing heat to maintain body temperature by burning glucose and fatty acids in a process called adaptive thermogenesis. The presence of an inducible thermogenic adipose tissue, and its beneficial effects for maintaining body weight and glucose and lipid homeostasis, has raised intense interest in understanding the regulation of thermogenesis. Elucidating the regulatory mechanisms underlying the thermogenic adipose program may provide excellent targets for therapeutics against obesity and diabetes. Here we review recent research on the role of epigenetics in the thermogenic gene program, focusing on DNA methylation and histone modifications.
Topics: Adipose Tissue, Brown; Animals; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Thermogenesis
PubMed: 27692461
DOI: 10.1016/j.tem.2016.09.003 -
Medecine Sciences : M/S Mar 2021DNA methylation is an epigenetic mechanism that has been largely probed regarding eukaryotic nuclear genome and bacteria, and its role is especially crucial in the... (Review)
Review
DNA methylation is an epigenetic mechanism that has been largely probed regarding eukaryotic nuclear genome and bacteria, and its role is especially crucial in the regulation of gene expression. In mammals, it is almost exclusively acting on a cytosine preceding a guanine (CpG), whereas it presents itself mainly in a non-CpG context in bacteria's DNA. Conversely to nuclear and bacterial genomes, the existence of methylation in the mitochondrial genome is still widely debated. This controversy has been attributed to structural differences between the nuclear and mitochondrial genomes, and to the techniques used to study methylation of cytosines, which were rather optimized for the study of nuclear DNA. However, novel studies suggest that cytosine methylation is truly existing in mitochondria, and that it is mostly found in a non-CpG context, just like in their evolutionary relative, the bacteria.
Topics: DNA Methylation; DNA, Mitochondrial
PubMed: 33739273
DOI: 10.1051/medsci/2021011 -
Biochemical Society Transactions Jun 2022DNA methylation is an epigenetic modification with a very long evolutionary history. However, DNA methylation evolves surprisingly rapidly across eukaryotes. The...
DNA methylation is an epigenetic modification with a very long evolutionary history. However, DNA methylation evolves surprisingly rapidly across eukaryotes. The genome-wide distribution of methylation diversifies rapidly in different lineages, and DNA methylation is lost altogether surprisingly frequently. The growing availability of genomic and epigenomic sequencing across organisms highlights this diversity but also illuminates potential factors that could explain why both the DNA methylation machinery and its genome-wide distribution evolve so rapidly. Key to this are new discoveries about the fitness costs associated with DNA methylation, and new theories about how the fundamental biochemical mechanisms of DNA methylation introduction and maintenance could explain how new genome-wide patterns of methylation evolve.
Topics: DNA Methylation; Epigenesis, Genetic; Epigenomics; Eukaryota; Eukaryotic Cells
PubMed: 35521905
DOI: 10.1042/BST20210725 -
Seminars in Cell & Developmental Biology Feb 2017Osteoarthritis (OA) is a chronic musculoskeletal disease characterised by the destruction of articular cartilage, synovial inflammation and bone remodelling. Disease... (Review)
Review
Osteoarthritis (OA) is a chronic musculoskeletal disease characterised by the destruction of articular cartilage, synovial inflammation and bone remodelling. Disease aetiology is complex and highly heritable, with genetic variation estimated to contribute to 50% of OA occurrence. Epigenetic alterations, including DNA methylation changes, have also been implicated in OA pathophysiology. This review examines what genetic and DNA methylation studies have taught us about the genes and pathways involved in OA pathology. The influence of DNA methylation on the molecular mechanisms underlying OA genetic risk and the consequence of this interaction on disease susceptibility and penetrance are also discussed.
Topics: Animals; DNA Methylation; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Osteoarthritis
PubMed: 27130636
DOI: 10.1016/j.semcdb.2016.04.017