Arsenic methylation and microbial communities in paddy soils under alternating anoxic and oxic conditions.

Arsenic (As) methylation in soils affects the environmental behavior of As, excessive accumulation of dimethylarsenate (DMA) in rice plants leads to straighthead disease and a serious drop in crop yield. Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security. Here, soils including un-arsenic contaminated (N-As), low-arsenic (L-As), medium-arsenic (M-As), and high-arsenic (H-As) soils were incubated under continuous anoxic, continuous oxic, and consecutive anoxic/oxic treatments respectively, to profile arsenic methylating process and microbial species involved in the As cycle. Under anoxic-oxic (A-O) treatment, methylated arsenic was significantly increased once oxygen was introduced into the incubation system. The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic (A), oxic (O), and oxic-anoxic (O-A) treatments, under which arsenic was methylated slightly and then decreased in all four As concentration soils. In fact, the most plentiful arsenite S-adenosylmethionine methyltransferase genes (arsM) contributed to the increase in As methylation. Proteobacteria (40.8%-62.4%), Firmicutes (3.5%-15.7%), and Desulfobacterota (5.3%-13.3%) were the major microorganisms related to this process. These microbial increased markedly and played more important roles after oxygen was introduced, indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic (flooding) and oxic (drainage) environment. The novel findings provided new insights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.

The response to influenza vaccination is associated with DNA methylation-driven regulation of T cell innate antiviral pathways.

BACKGROUND: The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell-type composition. RESULTS: Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019-2020 and 2020-2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test. CONCLUSIONS: Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.

Research trend of lung cancer epigenetics research: Bibliometric and visual analysis of top-100 cited documents.

Background: Lung cancer is a highly prevalent cancer on a global scale and its oncogenic process is driven by the accumulation of multiple pathological events. Epigenetics has gained significant recognition in recent years as a crucial contributor to the development of lung cancer. Epigenetics include processes such as DNA methylation, histone modification, chromatin remodeling, and RNA modification. These pathways lead to enduring alterations in genetic phenotypes, which are crucial in the advancement and growth of lung cancer. However, the specific mechanisms and roles of epigenetics in lung cancer still need to be further elucidated. Methods: We obtained publications from the Web of Science databases and applied a rigorous search method to filter them. Ultimately, we gathered high-quality publications that had received the highest 100 number of citations. The data were processed and visualized by various bibliometric tools. Results: The 100 papers had varying numbers of citations, with the lowest being 491 and the most being 6316. On average, each work received 1119 citations. A total of 1056 co-authors were involved in publishing these papers in 59 journals from 185 institutions in 27 countries. The majority of high-caliber research in the subject of lung cancer epigenetics is conducted in advanced countries, with the United States taking the lead in terms of both the quantity of articles produced and their academic influence. The study of DNA methylation has been a longstanding research priority in the discipline. With the development of next-generation sequencing technology in recent years, research related to non-coding RNA has become a research hotspot. Future research directions may focus more on exploring the mechanisms of action of messenger RNA and circular RNA and developing targeted treatment strategies based on non-coding RNA drugs. Conclusion: We analyzed 100 top lung cancer and epigenetics documents through various bibliometric analysis tools. This study provides a concise overview of the findings from prior research, anticipates future research directions, and offers potential avenues for additional investigation.

Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation.

BACKGROUND: The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis. RESULTS: After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression. CONCLUSIONS: Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.

DNA methylation markers for oral cancer detection in non- and minimally invasive samples: a systematic review.

More than 50% of oral cancer (OC) patients are diagnosed with advanced-stage disease associated with poor prognosis and quality of life, supporting an urgent need to improve early OC detection. The identification of effective molecular markers by minimally invasive approaches has emerged as a promising strategy for OC screening. This systematic review summarizes and evaluates the performance of the DNA methylation markers identified in non- or minimally invasive samples for OC detection. PubMed's MEDLINE, Scopus, Embase, and Cochrane Library databases were systematically searched for studies that evaluated DNA methylation markers in non-invasive and/or minimally invasive samples (oral rinse/saliva, oral brush, and blood) from OC patients. Two investigators independently extracted data on study population characteristics, candidate methylation markers, testing samples, DNA methylation assay, and performance diagnostic outcomes. Methodological study quality was assessed with the Quality Assessment for Studies of Diagnostic Accuracy-2 tool. Thirty-one studies met the inclusion criteria for this systematic review. DNA methylation markers were evaluated in oral rinse/saliva (n = 17), oral brush (n = 9), and blood (n = 7) samples. Methylation-specific PCR (MSP) and quantitative-MSP were the most common DNA methylation assays. Regarding diagnostic performance values for salivary, oral brush, and blood DNA methylation markers, sensitivity and specificity ranged between 3.4-100% and 21-100%, 9-100% and 26.8-100%, 22-70% and 45.45-100%, respectively. Different gene methylation panels showed good diagnostic performance for OC detection. This systematic review discloses the promising value of testing DNA methylation markers in non-invasive (saliva or oral rinse) or minimally invasive (oral brush or blood) samples as a novel strategy for OC detection. However, further validation in large, multicenter, and prospective study cohorts must be carried out to confirm the clinical value of specific DNA methylation markers in this setting.

DNA Hyper-methylation Associated With Schizophrenia May Lead to Increased Levels of Autoantibodies.

Background and Hypothesis: Environmental stressors may influence immune surveillance in B lymphocytes and stimulate autoimmune responses via epigenetic DNA methylation modifications in schizophrenia (SCZ). Study Design: A total of 2722, Chinese Han origin subjects were recruited in this study (2005-2011), which included a discovery follow-up cohort with 40 remitters of SCZ (RSCZ), 40 nonremitters of SCZ (NRSCZ), and 40 controls (CTL), and a replication follow-up cohort (64 RSCZ, 16 NRSCZ, and 84 CTL), as well as a case-control validation cohort (1230 SCZ and 1208 CTL). Genomic DNA methylation, target gene mRNA transcripts, and plasma autoantibody levels were measured across cohorts. Study Results: We found extensive differences in global DNA methylation profiles between RSCZ and NRSCZ groups, wherein differential methylation sites (DMS) were enriched with immune cell maturation and activation in the RSCZ group. Out of 2722 participants, the foremost DMS cg14341177 was hyper-methylated in the SCZ group and it inhibited the alternative splicing of its target gene BICD2 and may have increased its autoantigen exposure, leading to an increase in plasma anti-BICD2 IgG antibody levels. The levels of cg14341177 methylation and anti-BICD2 IgG decreased significantly in RSCZ endpoint samples but not in NRSCZ endpoint samples. There are strong positive correlations between cg14341177 methylation, anti-BICD2 IgG, and positive and negative syndrome scale (PANSS) scores in the RSCZ groups, but not in the NRSCZ groups. Conclusions: These data suggest that abnormal DNA methylation could affect autoreactive responses in SCZ, and that cg14341177 methylation and anti-BICD2 IgG levels may potentially serve as useful biomarkers.

Global Characterization of DNA Methylation during Rice Leaf Angle Development.

During plant development and growth, genomic DNA accumulates chemical markers that determine the levels of gene expression. DNA methylation is an important epigenetic marker involved in plant developmental events. However, the characterization of the role of DNA methylation in rice leaf angle development has lagged behind. Herein, we performed bisulfite sequencing to characterize DNA methylation sites and performed transcriptome and small RNA sequencing during leaf angle development. The results revealed a global reduction in CG methylation during leaf angle establishment. A reduction in gene body CG methylation appears to play a vital role in leaf angle development. The hypomethylated and weakly expressed genes were functionally enriched in the brassinosteroid and auxin signaling pathways. Additionally, the main DNA methyltransferases were inactive. The addition of exogenous DNA methylation inhibitor 5-azacytidine increased the leaf angle, which confirmed that DNA methylation is crucial for leaf angle development. This study revealed a gradual decrease in 24-nucleotide siRNA levels during leaf angle development, particularly in relation to the enrichment of 24-nucleotide siRNAs at different hypomethylated regions that induce leaf angle inclination. Our results indicate crucial roles for DNA methylation in the rice leaf angle developmental stages.

Non-invasive diagnosis of pulmonary nodules by circulating tumor DNA methylation: A prospective multicenter study.

BACKGROUND: With the popularization of computed tomography, more and more pulmonary nodules (PNs) are being detected. Risk stratification of PNs is essential for detecting early-stage lung cancer while minimizing the overdiagnosis of benign nodules. This study aimed to develop a circulating tumor DNA (ctDNA) methylation-based, non-invasive model for the risk stratification of PNs. METHODS: A blood-based assay ("LUNG-TRAC") was designed to include novel lung cancer ctDNA methylation markers identified from in-house reduced representative bisulfite sequencing data and known markers from the literature. A stratification model was trained based on 183 ctDNA samples derived from patients with benign or malignant PNs and validated in 62 patients. LUNG-TRAC was further single-blindly tested in a single- and multi-center cohort. RESULTS: The LUNG-TRAC model achieved an area under the curve (AUC) of 0.810 (sensitivity = 74.4 % and specificity = 73.7 %) in the validation set. Two test sets were used to evaluate the performance of LUNG-TRAC, with an AUC of 0.815 in the single-center test (N = 61; sensitivity = 67.5 % and specificity = 76.2 %) and 0.761 in the multi-center test (N = 95; sensitivity = 50.7 % and specificity = 80.8 %). The clinical utility of LUNG-TRAC was further assessed by comparing it to two established risk stratification models: the Mayo Clinic and Veteran Administration models. It outperformed both in the validation and the single-center test sets. CONCLUSION: The LUNG-TRAC model demonstrated accuracy and consistency in stratifying PNs for the risk of malignancy, suggesting its utility as a non-invasive diagnostic aid for early-stage peripheral lung cancer. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov (NCT03989219).

Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11.

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation nonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, we explore the role of deubiquitinating enzyme RPN11 in NAFLD and NASH. Hepatocyte-specific RPN11 knockout mice are protected from diet-induced liver steatosis, insulin resistance, and steatohepatitis. Mechanistically, RPN11 deubiquitinates and stabilizes METTL3 to enhance the m6A modification and expression of acyl-coenzyme A (CoA) synthetase short-chain family member 3 (ACSS3), which generates propionyl-CoA to upregulate lipid metabolism genes via histone propionylation. The RPN11-METTL3-ACSS3-histone propionylation pathway is activated in the livers of patients with NAFLD. Pharmacological inhibition of RPN11 by Capzimin ameliorated NAFLD, NASH, and related metabolic disorders in mice and reduced lipid contents in human hepatocytes cultured in 2D and 3D. These results demonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment.

Novel PAX3::MAML3 fusion identified in alveolar rhabdomyosarcoma, using DNA methylation profiling to expand the genetic spectrum of "fusion-positive" cases.

Alveolar rhabdomyosarcoma (ARMS) with FOXO1 gene rearrangements is an aggressive pediatric rhabdomyosarcoma subtype that is prognostically distinct from embryonal rhabdomyosarcoma and fusion-negative ARMS. Herein, we report two cases of ARMS with PAX3::MAML3 fusions. The tumors arose in an infant and an adolescent as stage IV metastatic disease (by Children's Oncology Group staging system). Histologically, both cases were small round blue cell tumors arranged in vague nests and solid sheets that were diffusely positive for desmin and myogenin. By methylation profiling and unsupervised clustering analysis, the tumors clustered with ARMS with classic FOXO1 rearrangements and ARMS with variant PAX3::NCOA1/INO80D fusions, but not with biphenotypic sinonasal sarcoma (BSNS) with PAX3::MAML3/NCOA2/FOXO1/YAP1 fusions, nor with other small round blue cell tumors, including embryonal rhabdomyosarcoma. The differentially methylated genes between ARMS and BSNS were highly enriched in genes involved in myogenesis, and 21% of these genes overlap with target genes of the PAX3::FOXO1 fusion transcription factor. On follow-up after initiation of vincristine/actinomycin/cyclophosphamide chemotherapy, the tumors showed partial and complete clinical response, consistent with typical upfront chemotherapy responsiveness of ARMS with the classic FOXO1 rearrangement. We conclude that PAX3::MAML3 is a novel variant fusion of ARMS, which displays a methylation signature distinct from BSNS despite sharing similar PAX3 fusions. These findings highlight the utility of methylation profiling in classifying ARMS with non-canonical fusions.

Comparative DNA methylation reveals epigenetic adaptation to high altitude in snub-nosed monkeys.

DNA methylation plays a crucial role in environmental adaptations. Here, using whole-genome bisulfite sequencing, we generated comprehensive genome-wide DNA methylation profiles for the high-altitude Yunnan snub-nosed monkey ( Rhinopithecus bieti) and the closely related golden snub-nosed monkey ( R. roxellana). Our findings indicated a slight increase in overall DNA methylation levels in golden snub-nosed monkeys compared to Yunnan snub-nosed monkeys, suggesting a higher prevalence of hypermethylated genomic regions in the former. Comparative genomic methylation analysis demonstrated that genes associated with differentially methylated regions were involved in membrane fusion, vesicular formation and trafficking, hemoglobin function, cell cycle regulation, and neuronal differentiation. These results suggest that the high-altitude-related epigenetic modifications are extensive, involving a complete adaptation process from the inhibition of single Ca 2+ channel proteins to multiple proteins collaboratively enhancing vesicular function or inhibiting cell differentiation and proliferation. Functional assays demonstrated that overexpression or down-regulation of candidate genes, such as SNX10, TIMELESS, and CACYBP, influenced cell viability under stress conditions. Overall, this research suggests that comparing DNA methylation across closely related species can identify novel candidate genomic regions and genes associated with local adaptations, thereby deepening our understanding of the mechanisms underlying environmental adaptations.

Buccal DNA global methylation and cognitive performance in stunted children under 5 years of age.

The prevalence of stunting in Indonesian children under five years of age is about 20%. Chronic maternal malnutrition contributes to the risk of stunting by affecting global DNA methylation. In the present study, we aimed to evaluate the levels of 5-methyl-cytosine (5mC), as a surrogate marker of global DNA methylation, in buccal swabs and its potential association with risk of stunting and cognitive performance. The levels of 5mC were measured using the enzyme-linked immunosorbent assay. The Wechsler Preschool and Primary Scale of Intelligence was used to measure cognitive functions. Buccal swab DNA samples and anthropometric data were collected from a total of 231 children aged zero to five years. In this cross-sectional cohort, the prevalence of stunting was 37% in 138 children aged zero to two years and 30% in 93 children aged > two years. The univariable analysis revealed that the levels of 5mC in buccal swab DNA were significantly lower in severely stunted children (median, 2.84; interquartile range [IQR], 2.39-4.62; P-value, 0.0314) and in children of a younger age (median, 2.81; IQR 2.53-4.62, P-value, 0.0001) than in normal (median, 3.75; IQR, 2.80-4.74) and older children (median, 4.01, IQR, 3.39-4.87), respectively. We also found that the average cognitive scores tended to be low in boys and stunted children, although the differences were not statistically significant. Furthermore, levels of 5mC found in buccal and mouthwash DNA were not associated with cognitive scores.

An epigenome-wide study of selenium status and DNA methylation in the Strong Heart Study.

BACKGROUND: Selenium (Se) is an essential nutrient linked to adverse health endpoints at low and high levels. The mechanisms behind these relationships remain unclear and there is a need to further understand the epigenetic impacts of Se and their relationship to disease. We investigated the association between urinary Se levels and DNA methylation (DNAm) in the Strong Heart Study (SHS), a prospective study of cardiovascular disease (CVD) among American Indians adults. METHODS: Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry among 1,357 participants free of CVD and diabetes. DNAm in whole blood was measured cross-sectionally using the Illumina MethylationEPIC BeadChip (850 K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated cytosine-guanine dinucleotide (CpG) sites associated with urinary Se levels. RESULTS: The mean (standard deviation) urinary Se concentration was 51.8 (25.1) µg/g creatinine. Across 788,368 CpG sites, five differentially methylated positions (DMP) (hypermethylated: cg00163554, cg18212762, cg11270656, and hypomethylated: cg25194720, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top hypermethylated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Elastic net models selected 425 hypo- and hyper-methylated DMPs associated with urinary Se, including three sites (cg00163554 [DIP2C], cg18212762 [MAP4K2], cg11270656 [GPIHBP1]) identified in linear regressions. CONCLUSIONS: Urinary Se was associated with minimal changes in DNAm in adults from American Indian communities across the Southwest and the Great Plains in the United States, suggesting that other mechanisms may be driving health impacts. Future analyses should explore other mechanistic biomarkers in human populations, determine these relationships prospectively, and investigate the potential role of differentially methylated sites with disease endpoints.

DNA methylation in cardiovascular disease and heart failure: novel prediction models?

BACKGROUND: Cardiovascular diseases (CVD) affect over half a billion people worldwide and are the leading cause of global deaths. In particular, due to population aging and worldwide spreading of risk factors, the prevalence of heart failure (HF) is also increasing. HF accounts for approximately 36% of all CVD-related deaths and stands as the foremost cause of hospitalization. Patients affected by CVD or HF experience a substantial decrease in health-related quality of life compared to healthy subjects or affected by other diffused chronic diseases. MAIN BODY: For both CVD and HF, prediction models have been developed, which utilize patient data, routine laboratory and further diagnostic tests. While some of these scores are currently used in clinical practice, there still is a need for innovative approaches to optimize CVD and HF prediction and to reduce the impact of these conditions on the global population. Epigenetic biomarkers, particularly DNA methylation (DNAm) changes, offer valuable insight for predicting risk, disease diagnosis and prognosis, and for monitoring treatment. The present work reviews current information relating DNAm, CVD and HF and discusses the use of DNAm in improving clinical risk prediction of CVD and HF as well as that of DNAm age as a proxy for cardiac aging. CONCLUSION: DNAm biomarkers offer a valuable contribution to improving the accuracy of CV risk models. Many CpG sites have been adopted to develop specific prediction scores for CVD and HF with similar or enhanced performance on the top of existing risk measures. In the near future, integrating data from DNA methylome and other sources and advancements in new machine learning algorithms will help develop more precise and personalized risk prediction methods for CVD and HF.

Recurrent cervical cancer detection using DNA methylation markers in self-collected samples from home.

Early detection of recurrent cervical cancer is important to improve survival rates. The aim of this study was to explore the clinical performance of DNA methylation markers and high-risk human papillomavirus (HPV) in cervicovaginal self-samples and urine for the detection of recurrent cervical cancer. Cervical cancer patients without recurrence (n = 47) collected cervicovaginal self-samples and urine pre- and posttreatment. Additionally, 20 patients with recurrent cervical cancer collected cervicovaginal self-samples and urine at time of recurrence. All samples were self-collected at home and tested for DNA methylation and high-risk HPV DNA by PCR. In patients without recurrent cervical cancer, DNA methylation levels decreased 2-years posttreatment compared to pretreatment in cervicovaginal self-samples (p < .0001) and urine (p < .0001). DNA methylation positivity in cervicovaginal self-samples was more frequently observed in patients with recurrence (77.8%) than in patients without recurrence 2-years posttreatment (25.5%; p = .0004). Also in urine, DNA methylation positivity was more frequently observed in patients with recurrence (65%) compared to those without recurrence (35.6%; p = .038). Similarly, high-risk HPV positivity in both cervicovaginal self-samples and urine was more frequent (52.6% and 55%, respectively) in patients with recurrence compared to patients without recurrence (14.9% and 8.5%, respectively) (p = .004 and p = .0001). In conclusion, this study shows the potential of posttreatment monitoring of cervical cancer patients for recurrence by DNA methylation and high-risk HPV testing in cervicovaginal and urine samples collected at home. The highest recurrence detection rate was achieved by DNA methylation testing in cervicovaginal self-samples, detecting 77.8% of all recurrences and, specifically, 100% of the local recurrences.

METTL14 promotes chondrocyte ferroptosis in osteoarthritis via m6A modification of GPX4.

BACKGROUND: Ferroptosis is caused by iron-dependent peroxidation of membrane phospholipids and chondrocyte ferroptosis contributes to osteoarthritis (OA) progression. Glutathione peroxidase 4 (GPX4) plays a master role in blocking ferroptosis. N6-methyladenosine (m6A) is an epigenetic modification among mRNA post-transcriptional modifications. This study investigated the effect of methyltransferase-like 14 (METTL14), the key component of the m6A methyltransferase, on chondrocyte ferroptosis via m6A modification. METHODS: An OA rat model was established through an intra-articular injection of monosodium iodoacetate in the right knee. OA cartilages in rat models were used for gene expression analysis. Primary mouse chondrocytes or ADTC5 cells were stimulated with IL-1ß or erastin. The m6A RNA methylation quantification kit was used to measure m6A level. The effect of METTL14 and GPX4 on ECM degradation and ferroptosis was investigated through western blotting, fluorescence immunostaining, propidium iodide staining, and commercially available kits. The mechanism of METTL14 action was explored through MeRIP-qPCR assays. RESULTS: METTL14 and m6A expression was upregulated in osteoarthritic cartilages and IL-1ß-induced chondrocytes. METTL14 depletion repressed the IL-1ß or erastin-stimulated ECM degradation and ferroptosis in mouse chondrocytes. METTL14 inhibited GPX4 gene through m6A methylation modification. GPX4 knockdown reversed the si-METTL14-mediated protection in IL-1ß-induced chondrocytes. CONCLUSION: METTL14 depletion inhibits ferroptosis and ECM degradation by suppressing GPX4 mRNA m6A modification in injured chondrocytes.

FTO-mediated m 6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis.

The activation of hepatic stellate cells (HSCs) is central to the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSC activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals, and N 6-methyladenosine (m 6A) modification is closely related to autophagy. In this study, we find that the m 6A demethylase fat mass and obesity-associated protein (FTO), which is the m 6A methylase with the most significant difference in expression, is upregulated during HSC activation and bile duct ligation (BDL)-induced hepatic fibrosis. Importantly, we identify that FTO overexpression aggravates HSC activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is a target of FTO because FTO mainly mediates the m 6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and the activation of HSCs. Notably, the m 6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level by recognizing the m 6A binding site and ultimately inhibiting autophagy and HSC activation. Taken together, our findings highlight m6A-dependent ULK1 as an essential regulator of HSC autophagy and reveal that ULK1 is a novel potential therapeutic target for hepatic fibrosis treatment.

m5C RNA methylation: a potential mechanism for infectious Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by a variety of factors, including age, genetic susceptibility, cardiovascular disease, traumatic brain injury, and environmental factors. The pathogenesis of AD is largely associated with the overproduction and accumulation of amyloid-ß peptides and the hyperphosphorylation of tau protein in the brain. Recent studies have identified the presence of diverse pathogens, including viruses, bacteria, and parasites, in the tissues of AD patients, underscoring the critical role of central nervous system infections in inducing pathological changes associated with AD. Nevertheless, it remains unestablished about the specific mechanism by which infections lead to the occurrence of AD. As an important post-transcriptional RNA modification, RNA 5-methylcytosine (m5C) methylation regulates a wide range of biological processes, including RNA splicing, nuclear export, stability, and translation, therefore affecting cellular function. Moreover, it has been recently demonstrated that multiple pathogenic microbial infections are associated with the m5C methylation of the host. However, the role of m5C methylation in infectious AD is still uncertain. Therefore, this review discusses the mechanisms of pathogen-induced AD and summarizes research on the molecular mechanisms of m5C methylation in infectious AD, thereby providing new insight into exploring the mechanism underlying infectious AD.

CTHRC1 modulates cell proliferation and invasion in hepatocellular carcinoma by DNA methylation.

BACKGROUND: Collagen triple helix repeat containing-1 (CTHRC1), an extracellular matrix protein, is highly expressed in hepatocellular carcinoma (HCC) and linked to poor prognosis. Nevertheless, the precise mechanism of CTHRC1 in HCC is unclear. METHODS: Agena MassARRAY® Methylation Analysis assessed the methylation level of CTHRC1 in the promoter region. Functional assays were conducted to investigate the effects of CTHRC1 knockdown in Hep3B2.1 cells. RNA sequencing identified differentially expressed genes and lncRNAs associated with angiogenesis after CTHRC1 knockdown. Furthermore, differential alternative splicing (AS) and gene fusion events were analyzed using rMATS and Arriba. RESULTS: In HCC cell lines, CTHRC1 was highly expressed and associated with hypomethylation. Downregulation of CTHRC1 inhibited Hep3B2.1 cell proliferation, migration, and invasion, blocked cells in the G1/S phase, and promoted apoptosis. We obtained 34 mRNAs and 7 lncRNAs differentially expressed between the NC and CTHRC1 inhibitor groups. Additionally, we found 4 angiogenesis-related mRNAs and lncRNAs significantly correlated with CTHRC1. RT-qPCR results showed that knockdown of CTHRC1 in Hep3B2.1 cells resulted in significantly aberrant expression of CXCL6, LINC02127, and AC020978.8. Moreover, the role of CTHRC1 in HCC development may be associated with events, like 12 AS events and 5 pairs of fusion genes. CONCLUSIONS: High expressed CTHRC1 is associated with hypomethylation and may promote HCC development, involving events like angiogenesis, alternative splicing, and gene fusion.

Insights into heterosis from histone modifications in the flag leaf of inter-subspecific hybrid rice.

BACKGROUND: Inter-subspecific hybrid rice represents a significant breakthrough in agricultural genetics, offering higher yields and better resilience to various environmental stresses. While the utilization of these hybrids has shed light on the genetic processes underlying hybridization, understanding the molecular mechanisms driving heterosis remains a complex and ongoing challenge. Here, chromatin immunoprecipitation-sequencing (ChIP-seq) was used to analyze genome-wide profiles of H3K4me3 and H3K27me3 modifications in the inter-subspecific hybrid rice ZY19 and its parents, Z04A and ZHF1015, then combined them with the transcriptome and DNA methylation data to uncover the effects of histone modifications on gene expression and the contribution of epigenetic modifications to heterosis. RESULTS: In the hybrid, there were 8,126 and 1,610 different peaks for H3K4me3 and H3K27me3 modifications when compared to its parents, respectively, with the majority of them originating from the parental lines. The different modifications between the hybrid and its parents were more frequently observed as higher levels in the hybrid than in the parents. In ZY19, there were 476 and 84 allele-specific genes with H3K4me3 and H3K27me3 modifications identified, representing 7.9% and 12% of the total analyzed genes, respectively. Only a small portion of genes that showed differences in parental H3K4me3 and H3K27me3 modifications which demonstrated allele-specific histone modifications (ASHM) in the hybrid. The H3K4me3 modification level in the hybrid was significantly lower compared to the parents. In the hybrid, DNA methylation occurs more frequently among histone modification target genes. Additionally, over 62.58% of differentially expressed genes (DEGs) were affected by epigenetic variations. Notably, there was a strong correlation observed between variations in H3K4me3 modifications and gene expression levels in the hybrid and its parents. CONCLUSION: These findings highlight the substantial impact of histone modifications and DNA methylation on gene expression during hybridization. Epigenetic variations play a crucial role in controlling the differential expression of genes, with potential implications for heterosis.