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Neuroscience and Biobehavioral Reviews Jan 2024Smoking continues to be a leading cause of preventable disease and death worldwide. Nicotine dependence generates a lifelong propensity towards cravings and relapse,... (Review)
Review
Smoking continues to be a leading cause of preventable disease and death worldwide. Nicotine dependence generates a lifelong propensity towards cravings and relapse, presenting an ongoing challenge for the development of treatments. Accumulating evidence supports a role for epigenetics in the development and maintenance of addiction to many drugs of abuse, however, the involvement of epigenetics in nicotine dependence is less clear. Here we review evidence that nicotine interacts with epigenetic mechanisms to enable the maintenance of nicotine-seeking across time. Research across species suggests that nicotine increases permissive histone acetylation, decreases repressive histone methylation, and modulates levels of DNA methylation and noncoding RNA expression throughout the brain. These changes are linked to the promoter regions of genes critical for learning and memory, reward processing and addiction. Pharmacological manipulation of enzymes that catalyze core epigenetic modifications regulate nicotine reward and associative learning, demonstrating a functional role of epigenetic modifications in nicotine dependence. These findings are consistent with nicotine promoting an overall permissive chromatin state at genes important for learning, memory and reward. By exploring these links through next-generation sequencing technologies, epigenetics provides a promising avenue for future interventions to treat nicotine dependence.
Topics: Humans; Histones; Nicotine; Tobacco Use Disorder; Epigenesis, Genetic; DNA Methylation
PubMed: 38070842
DOI: 10.1016/j.neubiorev.2023.105505 -
Advanced Science (Weinheim,... Jul 2023Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset...
Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3 promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1 is further found to bind to the HyperM region of SHANK3 promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1 on the expression of SHANK3 is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3 expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3 in PBMCs can serve as a potential peripheral biomarker of SCZ.
Topics: Humans; DNA Methylation; Leukocytes, Mononuclear; Schizophrenia; Interneurons; DNA; Y-Box-Binding Protein 1; Nerve Tissue Proteins
PubMed: 37211699
DOI: 10.1002/advs.202300455 -
Epigenetics Dec 2023The CRISPR/dCas9-based epigenome editing technique has driven much attention. Fused with a catalytic domain from Dnmt or Tet protein, the CRISPR/dCas9-DnmtCD or -TetCD...
The CRISPR/dCas9-based epigenome editing technique has driven much attention. Fused with a catalytic domain from Dnmt or Tet protein, the CRISPR/dCas9-DnmtCD or -TetCD systems possess the targeted DNA methylation editing ability and have established a series of and disease models. However, no publication has been reported on zebrafish (), an important animal model in biomedicine. The present study demonstrated that CRISPR/dCas9-Dnmt7 and -Tet2 catalytic domain fusions could site-specifically edit genomic DNA methylation in zebrafish and may serve as an efficient toolkit for DNA methylation editing in the zebrafish model.
Topics: Animals; DNA Methylation; CRISPR-Cas Systems; Gene Editing; Zebrafish; Epigenome
PubMed: 36945831
DOI: 10.1080/15592294.2023.2192326 -
Trends in Genetics : TIG Jan 2024First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across... (Review)
Review
First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across tissues derived from different germ layers within a given individual. This property, termed systemic interindividual variation (SIV), is attributed to stochastic methylation establishment before germ layer differentiation. Evidence suggests that some putative human MEs are sensitive to environmental exposures in early development. In this review we introduce key concepts pertaining to human MEs, describe methods used to identify MEs in humans, and review their genomic features. We also highlight studies linking DNAm at putative human MEs to early environmental exposures and postnatal (including disease) phenotypes.
Topics: Humans; Animals; Mice; Epigenesis, Genetic; DNA Methylation; Phenotype; Genomics; Alleles
PubMed: 38000919
DOI: 10.1016/j.tig.2023.09.007 -
Current Obesity Reports Dec 2023Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review... (Review)
Review
PURPOSE OF REVIEW
Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review highlights current research and its challenges in genetics and epigenetics of obesity.
RECENT FINDINGS
Recent progress in genetics of polygenic traits, particularly represented by genome-wide association studies, led to the discovery of hundreds of genetic variants associated with obesity, which allows constructing polygenic risk scores (PGS). In addition, epigenome-wide association studies helped identifying novel targets and methylation sites being important in the pathophysiology of obesity and which are essential for the generation of methylation risk scores (MRS). Despite their great potential for predicting the individual risk for obesity, the use of PGS and MRS remains challenging. Future research will likely discover more loci being involved in obesity, which will contribute to better understanding of the complex etiology of human obesity. The ultimate goal from a clinical perspective will be generating highly robust and accurate prediction scores allowing clinicians to predict obesity as well as individual responses to body weight loss-specific life-style interventions.
Topics: Humans; DNA Methylation; Genome-Wide Association Study; Epigenesis, Genetic; Obesity; Phenotype; Genetic Risk Score
PubMed: 37819541
DOI: 10.1007/s13679-023-00526-z -
Nature Communications Jul 2023TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly...
TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood. Here we show that ablation of TET2/3 in intestinal epithelial cells results in a murine phenotype characterized by a severe homeostasis imbalance in the small intestine. Tet2/3-deleted mice show a pronounced loss of mature Paneth cells as well as fewer Tuft and more Enteroendocrine cells. Further results show major changes in DNA methylation at putative enhancers, which are associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescues the methylation and cellular defects. TET2/3 loss also alters the microbiome, predisposing the intestine to inflammation under homeostatic conditions and acute inflammation-induced death. Together, our results uncover previously unrecognized critical roles for DNA demethylation, possibly occurring subsequently to chromatin opening during intestinal development, culminating in the establishment of normal intestinal crypts.
Topics: Animals; Mice; Cell Differentiation; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Homeostasis; Inflammation; Intestine, Small
PubMed: 37414790
DOI: 10.1038/s41467-023-39512-3 -
Potential applications of DNA methylation testing technology in female tumors and screening methods.Biochimica Et Biophysica Acta. Reviews... Sep 2023DNA methylation is a common epigenetic modification, and the current commonly used methods for DNA methylation detection include methylation-specific PCR,... (Review)
Review
DNA methylation is a common epigenetic modification, and the current commonly used methods for DNA methylation detection include methylation-specific PCR, methylation-sensitive restriction endonuclease-PCR, and methylation-specific sequencing. DNA methylation plays an important role in genomic and epigenomic studies, and combining DNA methylation with other epigenetic modifications, such as histone modifications, may lead to better DNA methylation. DNA methylation also plays an important role in the development of disease, and analyzing changes in individual DNA methylation patterns can provide individualized diagnostic and therapeutic solutions. Liquid biopsy techniques are also increasingly well established in clinical practice and may provide new methods for early cancer screening. It is important to find new screening methods that are easy to perform, minimally invasive, patient-friendly, and affordable. DNA methylation mechanisms are thought to have an important role in cancer and have potential applications in the diagnosis and treatment of female tumors. This review discussed early detection targets and screening methods for common female tumors such as breast, ovarian, and cervical cancers and discussed advances in the study of DNA methylation in these tumors. Although existing screening, diagnostic, and treatment modalities exist, the high morbidity and mortality rates of these tumors remain challenging.
Topics: Humans; Female; DNA Methylation; Epigenesis, Genetic; Uterine Cervical Neoplasms; Genomics; Liquid Biopsy
PubMed: 37329994
DOI: 10.1016/j.bbcan.2023.188941 -
Epigenetics Dec 2023Abnormal DNA methylation is a fundamental characterization of epigenetics in cancer. Here we demonstrate that aberrant DNA methylating can modulate the tumour immune...
Abnormal DNA methylation is a fundamental characterization of epigenetics in cancer. Here we demonstrate that aberrant DNA methylating can modulate the tumour immune microenvironment in 16 cancer types. Differential DNA methylation in promoter region can regulate the transcriptomic pattern of immune-related genes and DNA hypomethylation mainly participated in the processes of immunity, carcinogenesis and immune infiltration. Moreover, many cancer types shared immune-related functions, like activation of innate immune response, interferon gamma response and NOD-like receptor signalling pathway. DNA methylation can further help identify molecular subtypes of kidney renal clear cell carcinoma. These subtypes are characterized by DNA methylation pattern, major histocompatibility complex, cytolytic activity and cytotoxic t lymphocyte and tumour mutation burden, and subtype with hypomethylation pattern shows unstable immune status. Then, we investigate the DNA methylation pattern of exhaustion-related marker genes and further demonstrate the role of hypomethylation in tumour immune microenvironment. In summary, our findings support the use of hypomethylation as a biomarker to understand the mechanism of tumour immune environment.
Topics: Humans; DNA Methylation; Neoplasms; Epigenesis, Genetic; Biomarkers, Tumor; Immunity; Tumor Microenvironment
PubMed: 36945884
DOI: 10.1080/15592294.2023.2192894 -
ELife Mar 2024A technique called mSTARR-seq sheds light on how DNA methylation may shape responses to external stimuli by altering the activity of sequences that control gene...
A technique called mSTARR-seq sheds light on how DNA methylation may shape responses to external stimuli by altering the activity of sequences that control gene expression.
Topics: Epigenesis, Genetic; DNA Methylation; Gene Expression Regulation
PubMed: 38497535
DOI: 10.7554/eLife.96710 -
Clinical Epigenetics Sep 2023Acute myeloid leukaemia (AML) is a deadly disease characterised by the uncontrolled proliferation of immature myeloid cells within the bone marrow. Altered regulation of... (Review)
Review
BACKGROUND
Acute myeloid leukaemia (AML) is a deadly disease characterised by the uncontrolled proliferation of immature myeloid cells within the bone marrow. Altered regulation of DNA methylation is an important epigenetic driver of AML, where the hypoxic bone marrow microenvironment can help facilitate leukaemogenesis. Thus, interactions between epigenetic regulation and hypoxia signalling will have important implications for AML development and treatment.
MAIN BODY
This review summarises the importance of DNA methylation and the hypoxic bone marrow microenvironment in the development, progression, and treatment of AML. Here, we focus on the role hypoxia plays on signalling and the subsequent regulation of DNA methylation. Hypoxia is likely to influence DNA methylation through altered metabolic pathways, transcriptional control of epigenetic regulators, and direct effects on the enzymatic activity of epigenetic modifiers. DNA methylation may also prevent activation of hypoxia-responsive genes, demonstrating bidirectional crosstalk between epigenetic regulation and the hypoxic microenvironment. Finally, we consider the clinical implications of these interactions, suggesting that reduced cell cycling within the hypoxic bone marrow may decrease the efficacy of hypomethylating agents.
CONCLUSION
Hypoxia is likely to influence AML progression through complex interactions with DNA methylation, where the therapeutic efficacy of hypomethylating agents may be limited within the hypoxic bone marrow. To achieve optimal outcomes for AML patients, future studies should therefore consider co-treatments that can promote cycling of AML cells within the bone marrow or encourage their dissociation from the bone marrow.
Topics: Humans; DNA Methylation; Epigenesis, Genetic; Leukemia, Myeloid, Acute; Signal Transduction; Hypoxia; Tumor Microenvironment
PubMed: 37705055
DOI: 10.1186/s13148-023-01566-x