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Acta Neuropathologica Dec 2023Understanding age acceleration, the discordance between biological and chronological age, in the brain can reveal mechanistic insights into normal physiology as well as...
Understanding age acceleration, the discordance between biological and chronological age, in the brain can reveal mechanistic insights into normal physiology as well as elucidate pathological determinants of age-related functional decline and identify early disease changes in the context of Alzheimer's and other disorders. Histopathological whole slide images provide a wealth of pathologic data on the cellular level that can be leveraged to build deep learning models to assess age acceleration. Here, we used a collection of digitized human post-mortem hippocampal sections to develop a histological brain age estimation model. Our model predicted brain age within a mean absolute error of 5.45 ± 0.22 years, with attention weights corresponding to neuroanatomical regions vulnerable to age-related changes. We found that histopathologic brain age acceleration had significant associations with clinical and pathologic outcomes that were not found with epigenetic based measures. Our results indicate that histopathologic brain age is a powerful, independent metric for understanding factors that contribute to brain aging.
Topics: Humans; Child, Preschool; Aging; Brain; Epigenomics; Acceleration; Autopsy; Epigenesis, Genetic; DNA Methylation
PubMed: 37815677
DOI: 10.1007/s00401-023-02636-3 -
Annals of Medicine Dec 2023To investigate the prognostic value of N6-methyladenosine (m6A)-, 5-methylcytosine (m5C)-, and N1-methyladenosine (m1A)-related genes in cervical cancer (CESC) and...
PURPOSE
To investigate the prognostic value of N6-methyladenosine (m6A)-, 5-methylcytosine (m5C)-, and N1-methyladenosine (m1A)-related genes in cervical cancer (CESC) and predicting immunotherapy response.
METHODS
We downloaded cervical cancer mRNA expression profiles, clinical data, and m6A, m5C, m1A-related genes from public databases, and subjected them to serial bioinformatics analysis and clinical sample validation.
RESULTS
Differential analysis revealed 106 methylation-related differential genes (MEDs), including 44 differentially downregulated and 62 upregulated genes. We then obtained methylation models containing 10 genes by univariate and multifactorial COX analysis. High risk genes with HR > 1 include IQGAP3, PTBP1, STAC3, CUX1, SLC2A1, and CA2, and low risk genes with HR < 1 include IGBP1, DUOX1, CHAF1A, and STAC3. We verified the accuracy of the model from inside TCGA and outside GSE39001 (AUC = 0.729). K-M analysis showed shorter survival times in the High-risk group, and Immunocytic infiltration analysis showed model genes closely associated with six immune cells. The high-risk group may benefit more effectively from immunosuppressive therapy, especially anti-CTLA-4 therapy ( < .05). We also screened nine drugs for potential treatment and verified the expression of three key genes SLC2A1, CUX1, and CA2 using immunohistochemistry and RT-qPCR experiments with clinical samples.
CONCLUSION
We identified a prognostic model using m6A/m5C/m1A-related genes in cervical cancer, which can predict survival time and correlate with immune cell infiltration. Additionally, anti-CTLA-4 may be used as an immunotherapeutic agent for cervical cancer.KEY MESSAGESCervical cancer still has a high mortality rate, we aim to establish a strong prognostic index and new treatment goals for improving patient survival.The role of three types of RNA methylation modifications, m6A, m5C, and m1A, in cervical cancer, remains unknown. Therefore, it is essential to explore the potential molecular mechanisms of m6A, m5C, and m1A methylation regulation in cervical cancer.We also screened nine drugs for potential treatment and anti-CTLA-4 may be used as an immunotherapeutic agent for cervical cancer. We verified the expression of three key genes SLC2A1, CUX1, and CA2.
Topics: Humans; Female; Methylation; Uterine Cervical Neoplasms; Prognosis; Immunotherapy; RNA; Heterogeneous-Nuclear Ribonucleoproteins; Polypyrimidine Tract-Binding Protein; GTPase-Activating Proteins
PubMed: 37042849
DOI: 10.1080/07853890.2023.2190618 -
Clinical Epigenetics Aug 2023Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and...
BACKGROUND
Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and cardiometabolic disorders later in life. This process has been attributed partly to DNA methylation modifications in growth and stress-related pathways. Nutrients involved with one-carbon metabolism (OCM), such as folate, choline, betaine, and vitamin B, provide methyl groups for DNA methylation of these pathways. Therefore, this study aimed to determine whether maternal OCM nutrient intakes and levels modified fetal DNA methylation and in turn altered fetal growth patterns in pregnancies with and without GDM.
RESULTS
In this prospective study at a single academic institution from September 2016 to June 2019, we recruited 76 pregnant women with and without GDM at 25-33 weeks gestational age and assessed their OCM nutrient intake by diet recalls and measured maternal blood OCM nutrient levels. We also collected placenta and cord blood samples at delivery to examine fetal tissue DNA methylation of the genes that modify fetal growth and stress response such as insulin-like growth factor 2 (IGF2) and corticotropin-releasing hormone (CRH). We analyzed the association between maternal OCM nutrients and fetal DNA methylation using a generalized linear mixed model. Our results demonstrated that maternal choline intake was positively correlated with cord blood CRH methylation levels in both GDM and non-GDM pregnancies (r = 0.13, p = 0.007). Further, the downstream stress hormone cortisol regulated by CRH was inversely associated with maternal choline intake (r = - 0.36, p = 0.021). Higher maternal betaine intake and serum folate levels were associated with lower cord blood and placental IGF2 DNA methylation (r = - 0.13, p = 0.049 and r = - 0.065, p = 0.034, respectively) in both GDM and non-GDM pregnancies. Further, there was an inverse association between maternal betaine intake and birthweight of infants (r = - 0.28, p = 0.015).
CONCLUSIONS
In conclusion, we observed a complex interrelationship between maternal OCM nutrients and fetal DNA methylation levels regardless of GDM status, which may, epigenetically, program molecular pathways related to fetal growth and stress response.
Topics: DNA Methylation; Humans; Female; Diabetes, Gestational; Pregnancy; Fetus; Folic Acid; Promoter Regions, Genetic; Prospective Studies
PubMed: 37633918
DOI: 10.1186/s13148-023-01554-1 -
Nature Communications Jul 2023Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological...
Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of the Bacteroides fragilis group (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = 383) and panepigenomic (n = 268) analysis of clinical BFG isolates cultured from infections seen at the NIH Clinical Center over four decades. Our analysis reveals that single BFG species harbor hundreds of DNA methylation motifs, with most individual motif combinations occurring uniquely in single isolates, implying immense unsampled methylation diversity within BFG epigenomes. Mining of BFG genomes identified more than 6000 methyltransferase genes, approximately 1000 of which were associated with intact prophages. Network analysis revealed substantial gene flow among disparate phage genomes, implying a role for genetic exchange between BFG phages as one of the ultimate sources driving BFG epigenome diversity.
Topics: Humans; Methyltransferases; Bacteroides fragilis; Epigenomics; DNA Methylation; Bacteriophages; Bacteroides; Epigenesis, Genetic
PubMed: 37429841
DOI: 10.1038/s41467-023-39892-6 -
Cancer Biology & Therapy Dec 2023Epitranscriptome studies have shown that critical RNA modifications drive tumorigenicity; however, the role of 5-methylcytosine (mC) RNA methylation remains poorly...
Epitranscriptome studies have shown that critical RNA modifications drive tumorigenicity; however, the role of 5-methylcytosine (mC) RNA methylation remains poorly understood. We extracted 17 mC regulators and clustered distinct mC modification patterns by consensus clustering analysis. Gene set variation and single-sample gene set enrichment analysis were applied to quantify functional analysis and immune infiltration. The least absolute shrinkage and selection operator was employed to develop a prognostic risk score. Kaplan-Meier with log-rank test was used for survival analysis. Differential expression analysis was performed with the "limma" R package. Wilcoxon signed ranked test or Kruskal-Wallis test was used to compare groups. We observed that mC RNA methylation was commonly upregulated in gastrointestinal cancer and related to prognosis. Clusters were identified for mC patterns, with distinct immune infiltrations and functional pathways. The risk scores of mC regulators were independent risk factors. Differentially expressed mRNAs (DEmRNAs) in mC clusters were involved in cancer-related pathways. The methylation-based mCscore showed a significant effect on the prognosis. Patients with a lower mCscore exhibited more therapeutic efficiency on anti-CTLA4 therapy in liver cancer, while the combination of anti-CTLA4 therapy and pd1 was more efficient for patients with a lower mCscore in pancreatic cancer. We uncovered dysregulations of mC-related regulators in gastrointestinal cancer and their associations with overall survival. Some immune cells were differently infiltrated in distinct mC modification patterns, indicating their potential impacts on gastrointestinal cancer cell-immune. Moreover, an mCscore, derived from DEmRNAs in specific clusters, can serve as a classifier for immunotherapy.
Topics: Humans; Methylation; Gastrointestinal Neoplasms; Pancreatic Neoplasms; Liver Neoplasms; RNA; Prognosis
PubMed: 37332118
DOI: 10.1080/15384047.2023.2223382 -
Epigenetics Dec 2023Increasing evidence has uncovered the essential roles of long noncoding RNAs (lncRNAs) in biological and pathological functions of dendritic cells (DCs) among patients...
Increasing evidence has uncovered the essential roles of long noncoding RNAs (lncRNAs) in biological and pathological functions of dendritic cells (DCs) among patients with systemic lupus erythematosus (SLE). However, whether lncRNA nuclear paraspeckle assembly transcript 1 () could modulate DCs, especially in the inflammation of SLE, remains largely unknown. Fifteen SLE patients and fifteen age-matched healthy controls were included, and their monocyte-derived dendritic cells (moDCs) were cultured in vitro. Our research identified that the expression of was significantly increased in moDCs of SLE patients and positively correlated with disease activity. Interleukin 6 (IL-6) from both plasma and secreted supernatants of moDCs was also elevated in the SLE group. In addition, regulation of in moDCs by transfection could lead to the corresponding change in IL-6 generation. While for , a micro-RNA that can bind with the 3' UTR region of and , it may serve as a negative modulator since its overexpression could result in the reduction of IL-6 levels and vice versa. Additionally, the elevation in expression could increase the secretion of IL-6 by specifically binding to , reducing the negative modulatory effects of on the target gene, which suggested that elevated expression could function as the competing endogenous RNA (ceRNA). In conclusion, our findings indicate that can efficiently sponge to upregulate expression and secretion of IL-6 in moDCs, suggesting that the axis may be involved in the development of SLE disease.
Topics: Humans; Dendritic Cells; DNA Methylation; Interleukin-6; Lupus Erythematosus, Systemic; MicroRNAs; Monocytes; RNA, Long Noncoding
PubMed: 37343193
DOI: 10.1080/15592294.2023.2226492 -
Nature Communications Nov 2023Internal modifications of mRNA have emerged as widespread and versatile regulatory mechanism to control gene expression at the post-transcriptional level. Most of these...
Internal modifications of mRNA have emerged as widespread and versatile regulatory mechanism to control gene expression at the post-transcriptional level. Most of these modifications are methyl groups, making S-adenosyl-L-methionine (SAM) a central metabolic hub. Here we show that metabolic labeling with a clickable metabolic precursor of SAM, propargyl-selenohomocysteine (PSH), enables detection and identification of various methylation sites. Propargylated A, C, and G nucleosides form at detectable amounts via intracellular generation of the corresponding SAM analogue. Integration into next generation sequencing enables mapping of N-methyladenosine (mA) and 5-methylcytidine (mC) sites in mRNA with single nucleotide precision (MePMe-seq). Analysis of the termination profiles can be used to distinguish mA from 2'-O-methyladenosine (A) and N1-methyladenosine (mA) sites. MePMe-seq overcomes the problems of antibodies for enrichment and sequence-motifs for evaluation, which was limiting previous methodologies. Metabolic labeling via clickable SAM facilitates the joint evaluation of methylation sites in RNA and potentially DNA and proteins.
Topics: RNA, Messenger; RNA; Methylation; S-Adenosylmethionine; Antibodies
PubMed: 37935679
DOI: 10.1038/s41467-023-42832-z -
Haematologica Sep 2023
Topics: Humans; DNA Methylation; Epigenome; GATA2 Deficiency; GATA2 Transcription Factor
PubMed: 36815365
DOI: 10.3324/haematol.2022.282305 -
Epigenetics Dec 2023N6-Methyladenosine (mA) plays key roles in the regulation of biological functions and cellular mechanisms for ischaemia reperfusion (IR) injury in different organs....
N6-Methyladenosine (mA) plays key roles in the regulation of biological functions and cellular mechanisms for ischaemia reperfusion (IR) injury in different organs. However, little is known about the underlying mechanisms of mA-modified mRNAs in hepatic IR injury. In mouse models, liver samples were subjected to methylated RNA immunoprecipitation with high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). In total, 16917 mA peaks associated with 4098 genes were detected in the sham group, whereas 21,557 mA peaks associated with 5322 genes were detected in the IR group. There were 909 differentially expressed mA peaks, 863 differentially methylated transcripts and 516 differentially mA modification genes determined in both groups. The distribution of mA peaks was especially enriched in the coding sequence and 3'UTR. Furthermore, we identified a relationship between differentially mA methylated genes (fold change≥1.5/≤ 0.667, value≤0.05) and differentially expressed genes (fold change≥1.5 and value≤0.05) to obtain three overlapping predicted target genes (Fnip2, Phldb2, and Pcf11). Our study revealed a transcriptome-wide map of mA mRNAs in hepatic IR injury and might provide a theoretical basis for future research in terms of molecular mechanisms.
Topics: Animals; Mice; Transcriptome; DNA Methylation; Protein Processing, Post-Translational; 3' Untranslated Regions; RNA, Messenger; Reperfusion Injury
PubMed: 37066716
DOI: 10.1080/15592294.2023.2201716 -
Human Pathology Dec 2023Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer with an overall 5-year survival of around 10 %. New prognostic tools to stratify patients are...
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer with an overall 5-year survival of around 10 %. New prognostic tools to stratify patients are needed. Our main aim was to evaluate the prognostic value of overall copy number variation (CNV) burden in surgically treated PDAC. DNA extracted from 108 surgical PDAC specimens was examined to collect data on the genome-wide DNA methylation status of >850,000 CpG sites in promoter, gene body, and enhancer regions (Illumina Infinium Methylation EPIC BeadChip Kit). CNV profiles were obtained and all PDACs were stratified into one of three groups: Low, moderate, or high overall CNV burden. Tumors histologically showing a dominant conventional and/or tubulopapillary pattern in 60 %-100 % and 0-59 % were categorized as Group A and Group B as per Kalimuthu. We also performed targeted next-generation sequencing (NGS) and immunohistochemistry. High overall CNV burden held independent negative prognostic value with poor survival (HR 4.01 (95%CI 1.96-8.19), p = 0.00014) and was more frequent in Group B (p = 0.0003). Most frequent chromosomal arm-level aberrations were gains of 8q (29 %) and 1q (19 %) and losses of 17p (55 %), 18q (43 %), 6q (37 %), 9p (36 %), 6p (26 %), 19p (26 %), and 8p (25 %). Most frequent mutations found were in KRAS (95 %), TP53 (62 %), CDKN2A (24 %), SMAD4 (23 %), ATM (9 %), ARID1A (7 %), RNF43 (7 %), GNAS (6 %), and KDM6A (6 %). Group A PDACs showed more frequently KRAS variants other than Gly12Val and Gly12Asp (p = 0.012). Our data indicate that overall CNV burden using genome-wide methylation profiling may be a useful prognostic tool in surgically treated PDAC. Importantly, our approach, using data from genome-wide methylation profiling for analysis of overall CNV burden, can be performed on formalin-fixed and paraffin embedded PDAC tissues. Future studies should examine the prognostic value of overall CNV burden in unresectable PDAC.
Topics: Humans; DNA Copy Number Variations; Prognosis; Proto-Oncogene Proteins p21(ras); Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Chromosome Aberrations; Mutation; Adenocarcinoma; DNA Methylation
PubMed: 37977512
DOI: 10.1016/j.humpath.2023.11.002