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Iranian Journal of Immunology : IJI Jun 2024Ankylosing spondylitis (AS) is a chronic autoimmune disorder characterized by the fusion of vertebral joints and axial arthritis. The programmed death-1 (PD-1)...
BACKGROUND
Ankylosing spondylitis (AS) is a chronic autoimmune disorder characterized by the fusion of vertebral joints and axial arthritis. The programmed death-1 (PD-1) inhibitory receptor has a pivotal role in controlling T cell function and may have a significant impact on the pathogenesis of autoimmune diseases such as AS pathogenesis.
OBJECTIVE
To investigate PD-1 gene expression and its epigenetic regulation by detecting methylated CpG islands in the regulatory sites of the gene. This will provide insight into the mechanisms involved in the disease.
METHODS
30 AS patients and 30 healthy individuals were examined to detect the 16 CpG islands in intron 1 using bisulfite conversion and methylation-specific PCR technique. In addition, RNA samples were isolated from fresh peripheral blood mononuclear cells (PBMCs), and after complementary DNA (cDNA) synthesis, the expression level of the PD-1 gene was evaluated using Real-Time PCR.
RESULTS
The CpG islands located in the intronic zone of the PD-1 gene were hyper-methylated in both the patients with AS and the healthy controls. The gene expression of PD-1 was significantly downregulated in AS patients compared with the controls (p=0.017). A negative correlation between the Bath Ankylosing Spondylitis Disease Activity Index and PD-1 gene expression was also revealed.
CONCLUSION
The low level of PD-1 gene expression is implicated in the pathogenesis of AS. However, in both groups, the methylation level of the intron 1 CpG islands of the PD-1 gene suggests that other regulatory mechanisms are more relevant to PD-1 gene expression than methylation in the intron.
PubMed: 38912647
DOI: 10.22034/iji.2024.101565.2757 -
Journal of Cancer 2024Triple-negative breast cancer (TNBC) poses significant diagnostic challenges due to its aggressive nature. This research develops an innovative deep learning (DL) model...
Triple-negative breast cancer (TNBC) poses significant diagnostic challenges due to its aggressive nature. This research develops an innovative deep learning (DL) model based on the latest multi-omics data to enhance the accuracy of TNBC subtype and prognosis prediction. The study focuses on addressing the constraints of prior studies by showcasing a model with substantial advancements in data integration, statistical performance, and algorithmic optimization. Breast cancer-related molecular characteristic data, including mRNA, miRNA, gene mutations, DNA methylation, and magnetic resonance imaging (MRI) images, were retrieved from the TCGA and TCIA databases. This study not only compared single-omics with multi-omics machine learning models but also applied Bayesian optimization to innovatively optimize the neural network structure of a DL model for multi-omics data. The DL model for multi-omics data significantly outperformed single-omics models in subtype prediction, achieving a 98.0% accuracy in cross-validation, 97.0% in the validation set, and 91.0% in an external test set. Additionally, the MRI radiomics model showed promising performance, especially with the training set; however, a decrease in performance during transfer testing underscored the advantages of the DL model for multi-omics data in data consistency and digital processing. Our multi-omics DL model presents notable innovations in statistical performance and transfer learning capability, bearing significant clinical relevance for TNBC classification and prognosis prediction. While the MRI radiomics model proved effective, it requires further optimization for cross-dataset application to enhance accuracy and consistency. Our findings offer new insights into improving TNBC classification and prognosis through multi-omics data and DL algorithms.
PubMed: 38911381
DOI: 10.7150/jca.93215 -
Frontiers in Genetics 2024Breast cancer (BRCA) is one of the most common malignant tumors affecting women worldwide. DNA methylation modifications can influence oncogenic pathways and provide...
Breast cancer (BRCA) is one of the most common malignant tumors affecting women worldwide. DNA methylation modifications can influence oncogenic pathways and provide potential diagnostic and therapeutic targets for precision oncology. In this study, we used non-parametric permutation tests to identify differentially methylated positions (DMPs) between paired tumor and normal BRCA tissue samples from the Cancer Genome Atlas (TCGA) database. Then, we applied non-negative matrix factorization (NMF) to the DMPs to derive eight distinct DNA methylation signatures. Among them, signatures Hyper-S3 and Hypo-S4 signatures were associated with later tumor stages, while Hyper-S1 and Hypo-S3 exhibited higher methylation levels in earlier stages. Signature Hyper-S3 displayed an effect on overall survival. We further validated the four stage-associated signatures using an independent BRCA DNA methylation dataset from peripheral blood samples. Results demonstrated that 24 commonly hypomethylated sites in Hypo-S4 showed lower methylation in BRCA patients compared to healthy individuals, suggesting its potential as an early diagnostic biomarker. Furthermore, we found that methylation of 23 probes from four stage-related signatures exhibited predictive power for immune therapy response. Notably, methylation levels of all three probes from the Hypo-S4 and activity of the Hypo-S4 demonstrated highly positive relevance to PD-L1 gene expression, implying their significant predictive values for immunotherapy outcomes. GO and KEGG pathway enrichment analysis revealed that genes with these 23 immunotherapy-related methylation probes are mainly involved in glycan degradation or protein deglycosylation. These methylation signatures and probes may serve as novel epigenetic biomarkers for predicting tumor immunotherapy response. Our findings provide new insights into precision oncology approaches for BRCA.
PubMed: 38911294
DOI: 10.3389/fgene.2024.1403907 -
Frontiers in Molecular Biosciences 2024Protein methylation, similar to DNA methylation, primarily involves post-translational modification (PTM) targeting residues of nitrogen-containing side-chains and other... (Review)
Review
Protein methylation, similar to DNA methylation, primarily involves post-translational modification (PTM) targeting residues of nitrogen-containing side-chains and other residues. Protein arginine methylation, occurred on arginine residue, is mainly mediated by protein arginine methyltransferases (PRMTs), which are ubiquitously present in a multitude of organisms and are intricately involved in the regulation of numerous biological processes. Specifically, PRMTs are pivotal in the process of gene transcription regulation, and protein function modulation. Abnormal arginine methylation, particularly in histones, can induce dysregulation of gene expression, thereby leading to the development of cancer. The recent advancements in modification mediated by PRMTs and cancer research have had a profound impact on our understanding of the abnormal modification involved in carcinogenesis and progression. This review will provide a defined overview of these recent progression, with the aim of augmenting our knowledge on the role of PRMTs in progression and their potential application in cancer therapy.
PubMed: 38911125
DOI: 10.3389/fmolb.2024.1420365 -
Endocrine Journal Jun 2024Fibroblast growth factor (FGF) 21, a hormone produced by the liver, improves glucose and lipid metabolism. We recently demonstrated that the FGF21 gene (Fgf21) underwent...
Fibroblast growth factor (FGF) 21, a hormone produced by the liver, improves glucose and lipid metabolism. We recently demonstrated that the FGF21 gene (Fgf21) underwent DNA demethylation in the mouse liver via peroxisome proliferator-activated receptor (PPAR) α during the fetal to lactation periods. Furthermore, we found that the DNA methylation state of Fgf21 was involved in obesity in adult animals. In the present study, we analyzed the DNA methylation state of the FGF21 gene (FGF21) in obese patients using genomic DNA extracted from human monocytes and macrophages and investigated the pathophysiological significance of the FGF21 expression response to pemafibrate (PM), a PPARα ligand. We examined 67 patients with obesity stratified into in- and outpatient cohorts. A positive correlation was observed between serum FGF21 levels and triglyceride (TG) levels before PM administration. However, changes in serum FGF21 levels following PM administration did not correlate with the FGF21 DNA methylation rate, except at one CpG site. The body mass index (BMI) and serum TG levels positively correlated with the FGF21 DNA methylation rate, particularly at different CpG positions. A negative correlation was observed between absolute changes in serum FGF21 levels and the ratio of change in serum TG levels after PM administration. Collectively, these results indicate the potential of FGF21 DNA methylation as a surrogate indicator of BMI and serum TG levels, while absolute changes in serum FGF21 levels after PM administration may offer prognostic insights into the efficacy of reducing serum TG levels through PM administration.
PubMed: 38910123
DOI: 10.1507/endocrj.EJ23-0570 -
Clinical Epigenetics Jun 2024Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the...
BACKGROUND
Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the onset of puberty or the susceptibility to a wide range of diseases later in life. The present study aims to investigate changes in genomic DNA methylation profiles associated with pubertal onset analyzing human peripheral blood leukocytes from three different groups of subjects: 19 girls with central precocious puberty (CPP), 14 healthy prepubertal girls matched by age and 13 healthy pubertal girls matched by pubertal stage. For this purpose, the comparisons were performed between pre- and pubertal controls to identify changes in normal pubertal transition and CPP versus pre- and pubertal controls.
RESULTS
Analysis of methylation changes associated with normal pubertal transition identified 1006 differentially methylated CpG sites, 86% of them were found to be hypermethylated in prepubertal controls. Some of these CpG sites reside in genes associated with the age of menarche or transcription factors involved in the process of pubertal development. Analysis of methylome profiles in CPP patients showed 65% and 55% hypomethylated CpG sites compared with prepubertal and pubertal controls, respectively. In addition, interestingly, our results revealed the presence of 43 differentially methylated genes coding for zinc finger (ZNF) proteins. Gene ontology and IPA analysis performed in the three groups studied revealed significant enrichment of them in some pathways related to neuronal communication (semaphorin and gustation pathways), estrogens action, some cancers (particularly breast and ovarian) or metabolism (particularly sirtuin).
CONCLUSIONS
The different methylation profiles of girls with normal and precocious puberty indicate that regulation of the pubertal process in humans is associated with specific epigenetic changes. Differentially methylated genes include ZNF genes that may play a role in developmental control. In addition, our data highlight changes in the methylation status of genes involved in signaling pathways that determine the migration and function of GnRH neurons and the onset of metabolic and neoplastic diseases that may be associated with CPP in later life.
Topics: Humans; Puberty, Precocious; Female; DNA Methylation; Child; CpG Islands; Epigenesis, Genetic; Epigenome; Case-Control Studies
PubMed: 38909248
DOI: 10.1186/s13148-024-01683-1 -
Cell Death Discovery Jun 2024The physiological quantum of stress-inducible transcriptional protein, Lens Epithelium-Derived Growth Factor (LEDGF), is vital for the maintenance of cellular...
The physiological quantum of stress-inducible transcriptional protein, Lens Epithelium-Derived Growth Factor (LEDGF), is vital for the maintenance of cellular physiology. Erratic epigenetic reprogramming in response to oxidative stress or with advancing age is found to be a major cause in the gene silencing, leading to pathobiologies. Using aging human (h) eye lens/lens epithelial cells (LECs) coupled with redox-active Peroxiredoxin 6 (Prdx6)-deficient (Prdx6) mLECs as model systems, herein, we showed that in aging/oxidative stress, the human LEDGF gene was regulated by unique methylation patterns of CGs nucleotides within and around the Sp1 binding site(s) of CpG island of the LEDGF promoter (-170 to -27nts). The process caused the repression of LEDGF and its target, Hsp27, resulting in reactive oxygen species (ROS) amplification and cellular insults. This phenomenon was opposed to the unmethylated promoter in LECs. Clinically, we observed that the loss of LEDGF in the Prdx6 mLECs or aging lenses/LECs, correlating with increased expression of DNMT1, DNMT3a, and DNMT3b along with the methyl CpG binding protein 2 (MeCP2). Upon oxidative stress, the expression of these molecules was increased with the dramatic reduction in LEDGF expression. While demethylating agent, 5-Aza deoxycytidine (5-AzaC) transposed the aberrant methylation status, and revived LEDGF and Hsp27 expression. Mechanistically, the chloramphenicol acetyltransferase (CAT) reporter gene driven by the LEDGF promoter (-170/ + 35) and ChIP assays uncovered that 5-AzaC acted on GC/Sp1 sites to release LEDGF transcription. The data argued, for the first time, that de novo methylation of CGs around and within Sp1 sites of the CpG island directly disrupted Sp1 activity, which ensued in LEDGF repression and its biological functions. The findings should improve our understanding of cellular insults-associated with aberrant DNMTs-mediated LEDGF's activity, and can offer strategies for therapeutic intervention to halt aging/oxidative stress-induced abnormalities.
PubMed: 38909054
DOI: 10.1038/s41420-024-02076-2 -
Nature Communications Jun 2024The assignment of variants across haplotypes, phasing, is crucial for predicting the consequences, interaction, and inheritance of mutations and is a key step in...
The assignment of variants across haplotypes, phasing, is crucial for predicting the consequences, interaction, and inheritance of mutations and is a key step in improving our understanding of phenotype and disease. However, phasing is limited by read length and stretches of homozygosity along the genome. To overcome this limitation, we designed MethPhaser, a method that utilizes methylation signals from Oxford Nanopore Technologies to extend Single Nucleotide Variation (SNV)-based phasing. We demonstrate that haplotype-specific methylations extensively exist in Human genomes and the advent of long-read technologies enabled direct report of methylation signals. For ONT R9 and R10 cell line data, we increase the phase length N50 by 78%-151% at a phasing accuracy of 83.4-98.7% To assess the impact of tissue purity and random methylation signals due to inactivation, we also applied MethPhaser on blood samples from 4 patients, still showing improvements over SNV-only phasing. MethPhaser further improves phasing across HLA and multiple other medically relevant genes, improving our understanding of how mutations interact across multiple phenotypes. The concept of MethPhaser can also be extended to non-human diploid genomes. MethPhaser is available at https://github.com/treangenlab/methphaser .
Topics: Humans; Genome, Human; Haplotypes; DNA Methylation; Polymorphism, Single Nucleotide; Cell Line; Mutation
PubMed: 38909018
DOI: 10.1038/s41467-024-49588-0 -
BMJ Open Jun 2024Generation Scotland (GS) is a large family-based cohort study established as a longitudinal resource for research into the genetic, lifestyle and environmental...
PURPOSE
Generation Scotland (GS) is a large family-based cohort study established as a longitudinal resource for research into the genetic, lifestyle and environmental determinants of physical and mental health. It comprises extensive genetic, sociodemographic and clinical data from volunteers in Scotland.
PARTICIPANTS
A total of 24 084 adult participants, including 5501 families, were recruited between 2006 and 2011. Within the cohort, 59% (approximately 14 209) are women, with an average age at recruitment of 49 years. Participants completed a health questionnaire and attended an in-person clinic visit, where detailed baseline data were collected on lifestyle information, cognitive function, personality traits and mental and physical health. Genotype array data are available for 20 026 (83%) participants, and blood-based DNA methylation (DNAm) data for 18 869 (78%) participants. Linkage to routine National Health Service datasets has been possible for 93% (n=22 402) of the cohort, creating a longitudinal resource that includes primary care, hospital attendance, prescription and mortality records. Multimodal brain imaging is available in 1069 individuals.
FINDINGS TO DATE
GS has been widely used by researchers across the world to study the genetic and environmental basis of common complex diseases. Over 350 peer-reviewed papers have been published using GS data, contributing to research areas such as ageing, cancer, cardiovascular disease and mental health. Recontact studies have built on the GS cohort to collect additional prospective data to study chronic pain, major depressive disorder and COVID-19.
FUTURE PLANS
To create a larger, richer, longitudinal resource, 'Next Generation Scotland' launched in May 2022 to expand the existing cohort by a target of 20 000 additional volunteers, now including anyone aged 12+ years. New participants complete online consent and questionnaires and provide postal saliva samples, from which genotype and salivary DNAm array data will be generated. The latest cohort information and how to access data can be found on the GS website (www.generationscotland.org).
Topics: Humans; Scotland; Female; Male; Longitudinal Studies; Middle Aged; Adult; Family Health; Life Style; Aged; Young Adult; COVID-19; DNA Methylation; Mental Health; Health Status; Adolescent; SARS-CoV-2
PubMed: 38908846
DOI: 10.1136/bmjopen-2024-084719 -
The Journal of Investigative Dermatology Jun 2024Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. MC polyomavirus (MCPyV) causes 80% of MCCs, encoding the viral oncogenes small T...
Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. MC polyomavirus (MCPyV) causes 80% of MCCs, encoding the viral oncogenes small T (sT) and truncated large T antigens (tLT). These proteins impair the Rb1-dependent G1/S checkpoint blockade and subvert the host cell epigenome to promote cancer. Whole proteome analysis and proximal interactomics identified a tLT-dependent deregulation of DNA damage response (DDR). Our investigation revealed a previously unreported interaction between tLT and the histone methyltransferase EHMT2, to our knowledge. T Antigens knockdown reduced DDR protein levels and increased levels of the DNA damage marker γH2Ax. EHMT2 normally promotes H3K9 methylation and DDR signaling. Given that inhibition of EHMT2 did not significantly change the MCC cells proteome, tLT-EHMT2 interaction could affect the DDR. With tLT, we report that EHMT2 gained DNA damage repair proximal interactors. EHMT2 inhibition rescued proliferation in MCC cells depleted for their T antigens, suggesting impaired DDR and/or lack of checkpoint efficiency. Combined tLT and EHMT2 inhibition led to altered DDR, evidenced by multiple signaling alterations. Here we show that tLT hijacks multiple components of the DNA damage machinery to enhance tolerance to DNA damage in MCC cells, which could explain the genetic stability of these cancers.
PubMed: 38908781
DOI: 10.1016/j.jid.2024.04.034