DNA Methylation-related Genes Research Articles

Identification and functional analysis of DNA methylation-related enzyme gene family in Eleutherococcus senticosus

Eleutherococcus senticosus, a medicinal and edible plant recognized historically in East Asia, is characterized by a rich composition of saponins and other biologically active ingredients. In this study, 11 cytosine-5 DNA methyltransferases (C5-MTase) and 6 demethylases (dMTase) genes were identified within the genome of E. senticosus. Specifically, two major EsC5-MTases (EsMET1a and EsCMT3b) and two EsdMTases (EsROS1a and EsDME1) were screened through correlation analysis, examining the relationship between their gene expression levels and DNA methylation ratio within E. senticosus genome. Promoter function analysis revealed that the expression of these four prominent genes was regulated by abiotic stresses such as drought and light. In vitro catalytic validation demonstrated the functionality of EsMET1a, EsCMT3b, EsROS1a, and EsDME1 proteins in modifying DNA methylation patterns of key enzyme genes associated with saponin synthesis in E. senticosus. Additionally, transient in vivo overexpression of the four central genes could alter the saponin content by modulating the DNA methylation levels and secondary metabolic processes in E. senticosus. Molecular docking studies further elucidated the possible mechanism of DNA methylation and demethylation catalyzed by these four primary proteins.

Natural polymorphisms in ZMET2 encoding a DNA methyltransferase modulate the number of husk layers in maize.

DNA methylation affects agronomic traits and the environmental adaptability of crops, but the natural polymorphisms in DNA methylation-related genes and their contributions to phenotypic variation in maize (Zea mays) remain elusive. Here, we show that a polymorphic 10-bp insertion/deletion variant in the 3'UTR of Zea methyltransferase2 (ZMET2) alters its transcript level and accounts for variation in the number of maize husk layers. ZMET2 encodes a chromomethylase and is required for maintaining genome-wide DNA methylation in the CHG sequence context. Disruption of ZMET2 increased the number of husk layers and resulted in thousands of differentially methylated regions, a proportion of which were also distinguishable in natural ZMET2 alleles. Population genetic analyses indicated that ZMET2 was a target of selection and might play a role in the spread of maize from tropical to temperate regions. Our results provide important insights into the natural variation of ZMET2 that confers both global and locus-specific effects on DNA methylation, which contribute to phenotypic diversity in maize.

A prognostic model based on DNA methylation-related gene expression for predicting overall survival in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) continues to increase in morbidity and mortality among all types of cancer. DNA methylation, an important epigenetic modification, is associated with cancer occurrence and progression. The objective of this study was to establish a model based on DNA methylation risk scores for identifying new potential therapeutic targets in HCC and preventing cancer progression. Transcriptomic, clinical, and DNA methylation data on 374 tumor tissues and 50 adjacent normal tissues were downloaded from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma database. The gene expression profiles of the GSE54236 liver cancer dataset, which contains data on 161 liver tissue samples, were obtained from the Gene Expression Omnibus database. We analyzed the relationship between DNA methylation and gene expression levels after identifying the differentially methylated and expressed genes. Then, we developed and validated a risk score model based on the DNA methylation-driven genes. A tissue array consisting of 30 human hepatocellular carcinoma samples and adjacent normal tissues was used to assess the protein and mRNA expression levels of the marker genes by immunohistochemistry and qRT-PCR, respectively. Three methylation-related differential genes were identified in our study: GLS, MEX3B, and GNA14. The results revealed that their DNA methylation levels were negatively correlated with local gene expression regulation. The gene methylation levels correlated strongly with the prognosis of patients with liver cancer. This was confirmed by qRT-PCR and immunohistochemical verification of the expression of these genes or proteins in tumors and adjacent tissues. These results revealed the relationship between the level of relevant gene methylation and the prognosis of patients with liver cancer as well as the underlying cellular and biological mechanisms. This allows our gene signature to provide more accurate and appropriate predictions for clinical applications. Through bioinformatics analysis and experimental validation, we obtained three DNA methylation marker: GLS, MEX3B, and GNA14. This helps to predict the prognosis and may be a potential therapeutic target for HCC patients.

Co-Mutational Patterns with BCOR Influences Biological Characteristics and Clinical Outcomes of Myeloid Neoplasms

Introduction BCL6 co-repressor ( BCOR), a tumor suppressor gene located on chromosome X (locus Xp11.4) is involved in hematopoiesis via non-canonical polycomb repressive complex 1 (PRC1). The prevalence of BCOR mutation in myeloid neoplasms (MN) is approximately 5%, and it is also implicated in clonal hematopoiesis. In the 2022 ELN, WHO, and ICC classifications, BCOR is categorized as a myelodysplasia-related gene. Mutational patterns include frequent co-occurrence with DNMT3A and RUNX1 in AML and mutual exclusivity with NPM1 mutations. Although it has been theorized that BCORMT may cooperate preferentially with certain groups of genes, the prognostic significance of the BCOR co-mutational landscape has yet to be fully studied. Methods The total cohort (n = 20149) consists of 624 MN patients (169 primary (p) AML, 136 secondary (s) AML, 84 MDS, 34 MDS/MPN, 66 MPN, and 135 with other MN) from Karmanos Cancer Institute, publicly available metanalytic cohort consisting of various sub-studies (Awada et al., 2021; Kewan et al., 2023), and cohorts from open-access cancer genomics resource cBioPortal and AACR GENIE (v13.1) (Cerami et al., 2012; Gao et al., 2013). Clinical and genomic characteristics were reviewed. Chi-square and T-tests were used for analysis of various parameters as described, and Kaplan-Meier and log-rank methods were used to estimate overall survival (OS). The prevalence of BCORMT, co-occurring mutations, and their outcomes were analyzed based on co-mutational patterns. Results A total of 745 (3.7%) patients carried BCORMT. Male: Female ratio was 1.48, with a median age of 68 ys.(IQR 59-75). BCORMTshowed a trend to be most frequent in pAML compared to other MN (54 vs 46%, p=0.33). BCORMT was less associated with abnormal karyotype vs. BCORWT [41 vs. 51%, p=0.0002]. Median variant allele frequency (VAF) was 45% (IQR 22-69), and most mutations were frameshift (41%) followed by nonsense (27%), and missense (22%). Median OS was not different between BCORWT and BCORMT patients [21.9 vs. 19.6 mo., p=0.089] in the entire cohort. Oncoprint analysis centered around BCOR revealed frequent co-mutations with RUNX1, DNMT3A, TET2 and ASXL1. As a result, the patients were divided into 10 groups (groups A-J), and the OS was analyzed between groups and compared with BCORWT. Patients with BCOR/TET2, BCOR/RUNX1/TET2, and BCOR/ASXL1 (groups G, B, and H resp.) had the lowest median OS with 14.5 mo., 16.7 mo., and 17.4 mo., resp. However, no significant differences in median OS were observed between the compared groups except those involving BCOR/ASXL1 vs. BCOR/Others and BCORWT. BCOR/ASXL1 patients had significantly lower median OS compared to BCOR/Others [17.4 vs. 22.5 mo., p=0.022] and BCORWT [17.4 vs. 21.9 mo., p=0.017]. Further BCORMT and ASXL1MT comutational analysis irrespective of other co-occurring mutations, revealed that in those with BCORMT, ASXL1 co-mutation was seen in 143 (19.2%) patients. BCOR and ASXL1 co-mutation were primarily enriched in primary AML (49%), followed by sAML (25%). Median BCOR VAF was higher than ASXL1 [39 vs. 31%, p<0.0001]. The most associated mutational categories in this subgroup were related to myeloid transcription factors (TF) ( RUNX1, CEBPA; 62%), spliceosome ( SRSF2, U2AF1, SF3B1, ZRSR2; 22%), and DNA methylation family ( DNMT3A, TET2, IDH1/2; 8%). BCORMT/ ASXL1MT/DNA Methylation mutations had poorer median OS compared to BCORMT/ ASXL1MT/Spliceosome mutations [9.2 vs. 17.4 mo., p=0.044]. Whereas BCORMT/ ASXL1MT/Myeloid TF and BCORMT/ ASXL1MT/Spliceosome mutations had no significant survival difference compared to BCORWT, patients with BCORMT/ ASXL1MT/DNA Methylation had worse median OS [9.2 vs. 21.9 mo., p=0.007]. Conclusion This large cohort study confirms common BCOR co-mutation patterns and reveals prognostic differences in patients with co-occurring ASXL1 mutation. We demonstrated BCORMT with ASXL1MT without concurrent RUNX1MT, DNMT3AMT, and TET2MT had poorer overall survival. Furthermore, patients with BCORMT, ASXL1MT, and concomitant DNA methylation-related gene mutations had worse outcomes compared to those with concomitant spliceosome mutation and BCORWT. Our findings suggest that co-mutational patterns of BCOR may further clarify diagnosis and classification schemes, highlighting potential synergies among subcategories of gene mutations and their prognostic value.

Molecular characterizations and functional roles of NANOG in early development of porcine embryos

Nanog homeobox (NANOG) is the gateway to the pluripotent ground state in mouse embryonic stem cells and early embryos. However, understanding of the molecular signatures and functional characteristics of porcine NANOG remains limited. In this study, we analyzed the gene structure and sequence characteristics of porcine NANOG and found that the porcine NANOG gene is localized on chromosome 5, while NANOG sequence on chromosome 1 is the processed pseudogene. We explored the expression pattern of NANOG in porcine early embryos by immunofluorescence staining and Realtime-PCR and RNA-seq, the results showed that transcription of porcine NANOG commences at the 4-cell stage, while expression of the NANOG protein is initially observed in the inner cell mass of blastocysts. Furthermore, we identified a NANOG splicing variant in porcine early embryos, which maintain the overall structure of the original NANOG mRNA, except for a deletion of 38 base pairs in the second exon. To further investigate the function of NANOG in early embryo development in pigs, we employed siRNA-mediated deletion of the two specific transcripts on porcine zygotes. The results showed that blastocyst rate was significantly reduced after NANOG deleting. A significant decrease in the expression of DNA methylation-related gene DNMT3B was also observed in D3 embryo from the NANOG deleting group. In conclusion, the porcine NANOG gene, accompanied by a single-exon processed pseudogene, exhibits two transcripts and plays a pivotal role in the development of early-stage embryos.

DNA methylation regulator-mediated modification patterns and risk of intracranial aneurysm: a multi-omics and epigenome-wide association study integrating machine learning, Mendelian randomization, eQTL and mQTL data

BackgroundIntracranial aneurysms (IAs) pose a significant and intricate challenge. Elucidating the interplay between DNA methylation and IA pathogenesis is paramount to identify potential biomarkers and therapeutic interventions.MethodsWe employed a comprehensive bioinformatics investigation of DNA methylation in IA, utilizing a transcriptomics-based methodology that encompassed 100 machine learning algorithms, genome-wide association studies (GWAS), Mendelian randomization (MR), and summary-data-based Mendelian randomization (SMR). Our sophisticated analytical strategy allowed for a systematic assessment of differentially methylated genes and their implications on the onset, progression, and rupture of IA.ResultsWe identified DNA methylation-related genes (MRGs) and associated molecular pathways, and the MR and SMR analyses provided evidence for potential causal links between the observed DNA methylation events and IA predisposition.ConclusionThese insights not only augment our understanding of the molecular underpinnings of IA but also underscore potential novel biomarkers and therapeutic avenues. Although our study faces inherent limitations and hurdles, it represents a groundbreaking initiative in deciphering the intricate relationship between genetic, epigenetic, and environmental factors implicated in IA pathogenesis.Graphical

Analysis of CSF3R Gene Mutations and Clinical Characteristics in Patients with t(8;21) Acute Myeloid Leukemia

To investigate the occurrence of CSF3R mutation in patients with t(8;21) acute myeloid leukemia (AML) and its correlation with some clinical parameters. The clinical and laboratory data of 167 newly diagnosed AML patients with t(8;21) translocation were analyzed retrospectively. High-throughput DNA sequencing technology combined with Sanger sequencing method was used to detect 112 gene mutations. The occurrence of CSF3R gene mutation and its influence on the remission rate after chemotherapy were analyzed. Among 167 patients with t(8;21) AML, 15 patients (9.0%) carried CSF3R mutations, including 6 cases of membrane proximal region mutations and 9 cases of truncation mutations in the cytoplasmic tail. The most common coexisting mutations of CSF3R were KIT (40.0%), TET2 (33.3%), DNMT3A (26.7%), FLT3 (20.0%), CBL (20.0%), IDH1 (13.3%), etc. Compared with the wild type, the CSF3R mutant group had a higher mutation rate of DNA methylation-related genes（P <0.001）. The median peripheral white blood cell (WBC) count of patients with CSF3R gene mutation was 5.80 (3.20-8.56)×109/L at initial diagnosis, which was significantly lower than 8.80 (5.26-19.92)×109/L of the CSF3R wild-type patients (P =0.017). There was no significant difference between the two groups in sex, median age, FAB classification, hemoglobin level, platelet count, etc. (P >0.05). The CR rate of the CSF3R gene mutation group (100%) was significantly higher than that of the wild-type group (86.8%), but the difference was not statistically significant (P >0.05). The CSF3R gene mutation group had a significantly higher CD19 positive rate and a higher -X rate than the wild group (86.7% vs 47.4%, P =0.004; 33.3% vs 13.2%, P =0.037). There is a high incidence of CSF3R mutation in t (8;21) AML patients. The clinical characteristics and coexisting mutation genes of CSF3R mutation-positive patients are different from those of wild-type patients.

Persistence of Growth Enhancement Induced by Oxygen Plasma Irradiation Seed and Leaf

The variation of gene expression of seeds or leaves of Arabidopsis thaliana was investigated by irradiation with oxygen and air plasmas. The irradiation with oxygen plasma reported on the growth promotion and induced the consequence of gene expression in plant cells by neutral active oxygen species. The increase in leaf area ratio by oxygen plasma to seeds was due to epigenetics such as activation of DNA demethylation transcription factors and the growth enhancement effect induced by the plasma irradiation of seeds was inherited by next-generation cells through cell division even after germination. In oxygen irradiation for 10 s, expression of each de-DNA methylation-related gene increased, and DNA methylation-related genes decreased in expression. DNA acetylation that induces gene expressions was suppressed. However, irradiated for 20 s by oxygen, both demethylation suppression and promotion and methylation/acetylation suppression and promotion were obtained. On the other hand, methylation and demethylation may occur at the same time but were not significant and the acetylation was suppressed by air plasma irradiation. In both cases, active oxygen species was the key factor for the variation of gene expression.

DNMT3AR882H accelerates angioimmunoblastic T-cell lymphoma in mice.

DNA methylation-related genes, including TET2, IDH2, and DNMT3A are highly frequently mutated in angioimmunoblastic T-cell lymphoma (AITL), an aggressive malignancy of T follicular helper (Tfh) cells associated with aberrant immune features. It has been shown that TET2 loss cooperates with RHOAG17V to promote AITL in mice but the functional role of DNMT3A mutations in AITL remains unclear. Here, we report that DNMT3AR882H, the most common mutation of DNMT3A in AITL, accelerates the development of Tet2-/-; RHOAG17V AITL in mice, indicated by the expansion of malignant Tfh cells and aberrant B cells, skin rash, and significantly shortened disease-free survival. To understand the underlying cellular and molecular mechanisms, we performed single-cell transcriptome analyses of lymph nodes of mice transplanted with Tet2-/-, Tet2-/-; RHOAG17V or DNMT3AR882H; Tet2-/-; RHOAG17V hematopoietic stem and progenitor cells. These single-cell landscapes reveal that DNMT3A mutation further activates Tfh cells and leads to rapid and terminal differentiation of B cells, probably through enhancing the interacting PD1/PD-L1, ICOS/ICOSL, CD28/CD86, and ICAM1/ITGAL pairs. Our study establishes the functional roles of DNMT3A mutation in AITL and sheds light on the molecular mechanisms of this disease.

A novel DNA methylation-related gene signature for the prediction of overall survival and immune characteristics of ovarian cancer patients

BackgroundOvarian cancer (OC) is one of the most life-threatening cancers affecting women worldwide. Recent studies have shown that the DNA methylation state can be used in the diagnosis, treatment and prognosis prediction of diseases. Meanwhile, it has been reported that the DNA methylation state can affect the function of immune cells. However, whether DNA methylation-related genes can be used for prognosis and immune response prediction in OC remains unclear.MethodsIn this study, DNA methylation-related genes in OC were identified by an integrated analysis of DNA methylation and transcriptome data. Prognostic values of the DNA methylation-related genes were investigated through least absolute shrinkage and selection operator (LASSO) and Cox progression analyses. Immune characteristics were investigated by CIBERSORT, correlation analysis and weighted gene co-expression network analysis (WGCNA).ResultsTwelve prognostic genes (CA2, CD3G, HABP2, KCTD14, PI3, SERPINB5, SLAMF7, SLC9A2, STC2, TBP, TREML2 and TRIM27) were identified and a risk score signature and a nomogram based on prognostic genes and clinicopathological features were constructed for the survival prediction of OC patients in the training and two validation cohorts. Subsequently, the differences in the immune landscape between the high- and low-risk score groups were systematically investigated.ConclusionsTaken together, our study explored a novel efficient risk score signature and a nomogram for the survival prediction of OC patients. In addition, the differences of the immune characteristics between the two risk groups were clarified preliminarily, which will guide the further exploration of synergistic targets to improve the efficacy of immunotherapy in OC patients.

The ubiquitin-like, containing PHD and RING finger domains 1 (uhrf1) gene promotes ovarian development in Exopalaemon carinicauda

Ridgetail white prawn, Exopalaemon carinicauda, with high reproductive capacity can reproduce up to three or four generations a year. In exploring the genetic factors affecting the gonadal development of E. carinicauda, we cloned and studied the function of the ubiquitin-like, containing PHD and RING finger domains 1 (uhrf1) gene. The open reading frame of uhrf1 gene was 2286 bp, encoding a total of 761 amino acids. The Uhrf1 has UBL, TTD, PhD, SRA, and ring finger domains that are associated with genome methylation, histone recognition and chromatin modification. According to the phylogenetic analysis, the amino acid sequence of Ec-uhrf1 has the highest similarity with Litopenaeus vannamei uhrf1, and it is a branch of Penaeus monodon and L. vannamei. The real-time quantitative PCR showed that the expression level of uhrf1 was highest in ridgetail white prawn ovarian tissue, which was significantly higher than that of other tissues (P < 0.05). In addition, the expression level gradually increased in stages I-IV of ovarian development, with its expression level in stage IV being significantly higher than that in other stages (P < 0.05). RNAi results showed that a knockdown of uhrf1 gene expression significantly reduced the expression of the cell proliferation-related gene pcna, the DNA methylation-related gene dnmt1 and yolk synthesis related genes vg, indicating that uhrf1 regulates the expression of pcna and dnmt1. The in situ hybridization tests further indicated that the uhrf1 gene plays an important role in oocyte proliferation and accumulation of exogenous nutrients.

Induction of cytotoxic effects and changes in DNA methylation-related gene expression in a human fibroblast cell line by the metal-organic framework [H2NMe2]3 [Tb(III)(2,6 pyridinedicarboxylate)3] (Tb-MOF).

Lanthanide metal-organic frameworks (lanthanide MOFs) may be utilized for a variety of environmental and human health applications due to their luminescent properties and high thermal and water stability. However, the cytotoxic and epigenetic effects produced in human cells are not known. Therefore, we evaluated the cytotoxic effects, internalization, and changes in the mRNA abundance of DNA methylation and demethylation enzymes by exposing human fibroblast cells to a metal-organic framework [H2NMe2]3 [Tb(III)(2,6 pyridinedicarboxylate)3] (Tb-MOF). For this purpose, the cells were exposed to six concentrations (0.05 to 1.6mg/mL) of Tb-MOF for 48h. Field emission electron microscopy coupled to linear energy dispersive spectroscopy (FESEM‒EDS) and confocal microscopy analysis were performed. The cytotoxicity was determined with crystal violet and MTT assays. The results demonstrated the internalization of Tb-MOF at concentrations as low as 0.05mg/mL, as well as concentration-dependent toxicity. Additionally, we detected significant changes in the gene expression levels of DNA methyltransferases and demethylases due to the presence of Tb-MOF, suggesting that Tb-MOF could generate epigenetic changes even at low concentrations. The results of our study may establish a foundation for future research attempting to develop and apply secure nanomaterials (e.g., MOFs) to minimize damage to the environment and human health.

Assessment of ecotoxicity effects of aspirin on non-target organism (Daphnia magna) via analysis of the responses of oxidative stress, DNA methylation-related genes expressions and life traits changes.

Aspirin (acetylsalicylic acid, ASA), a widely used non-steroidal anti-inflammatory drug, was frequently detected in aquatic environments around the world. However, information on the potential toxic effects of aspirin on non-target aquatic invertebrates is limited. In the present study, we investigated the effects of ASA on the transcriptional expressions of antioxidant genes (Nrf2, Keap1, HO-1, GCLC, GPx, TRX, TrxR and Prx1) and DNA methylation genes (DNMT1, DNMT3 and TET2) in Daphnia magna (D. magna)for 24, 48 and 96 h and the changes of antioxidant enzymatic activity and GSH, MDA content for 48 h. The effects of ASA on the life traits of D. magna were also addressed via a 21-days chronic toxicity test. Results showed that the expressions of Nrf2 and its target genes (HO-1, GPx and TrxR, GCLC, TRX and Prx1) were induced to different degrees at 48 h and/or 96 h. The activity of antioxidant enzymes (SOD, CAT, GST and GPx) and MDA content increased but GSH content decreased, indicating that ASA caused oxidative stress in D. magna. ASA also changed the expression of DNA methylation genes, such as DNMT and TET2, in D. magna. We speculated that ASA may affect the antioxidant system responses through regulation of Nrf2/Keap1 signaling pathway, and/or through indirectly influencing DNA methylation levels by DNMT and TET gene expression, but the detailed mechanism needs further investigations. Chronic exposure to ASA for 21 days caused inhibitions on the growth, reproduction and behavior of D. magna (e.g., delaying days to the first brood and shortening the body length). In summary, ASA significantly affected the antioxidant responses of D. magna, and negatively disturbed its life traits in growth, development and reproduction.

Comprehensive bioinformatics analysis reveals biomarkers of DNA methylation-related genes in varicose veins.

Background: Patients with Varicose veins (VV) show no obvious symptoms in the early stages, and it is a common and frequent clinical condition. DNA methylation plays a key role in VV by regulating gene expression. However, the molecular mechanism underlying methylation regulation in VV remains unclear. Methods: The mRNA and methylation data of VV and normal samples were obtained from the Gene Expression Omnibus (GEO) database. Methylation-Regulated Genes (MRGs) between VV and normal samples were crossed with VV-associated genes (VVGs) obtained by weighted gene co-expression network analysis (WGCNA) to obtain VV-associated MRGs (VV-MRGs). Their ability to predict disease was assessed using receiver operating characteristic (ROC) curves. Biomarkers were then screened using a random forest model (RF), support vector machine model (SVM), and generalized linear model (GLM). Next, gene set enrichment analysis (GSEA) was performed to explore the functions of biomarkers. Furthermore, we also predicted their drug targets, and constructed a competing endogenous RNAs (ceRNA) network and a drug target network. Finally, we verified their mRNA expression using quantitative real-time polymerase chain reaction (qRT-PCR). Results: Total three VV-MRGs, namely Wnt1-inducible signaling pathway protein 2 (WISP2), Cysteine-rich intestinal protein 1 (CRIP1), and Odd-skipped related 1 (OSR1) were identified by VVGs and MRGs overlapping. The area under the curves (AUCs) of the ROC curves for these three VV-MRGs were greater than 0.8. RF was confirmed as the optimal diagnostic model, and WISP2, CRIP1, and OSR1 were regarded as biomarkers. GSEA showed that WISP2, CRIP1, and OSR1 were associated with oxidative phosphorylation, extracellular matrix (ECM), and respiratory system functions. Furthermore, we found that lncRNA MIR17HG can regulate OSR1 by binding to hsa-miR-21-5p and that PAX2 might treat VV by targeting OSR1. Finally, qRT-PCR results showed that the mRNA expression of the three genes was consistent with the results of the datasets. Conclusion: This study identified WISP2, CRIP1, and OSR1 as biomarkers of VV through comprehensive bioinformatics analysis, and preliminary explored the DNA methylation-related molecular mechanism in VV, which might be important for VV diagnosis and exploration of potential molecular mechanisms.

Effects of oocyte vitrification on gene expression in the liver and kidney tissues of adult offspring.

Oocyte vitrification is an important assisted reproductive technology (ART) that preserves the fertility of unmarried patients with malignant tumors, and promotes the development of the oocyte donation program. In recent years, the effects of ART, including the vitrification of oocytes and embryos on the health of offspring, have attracted much attention; however, it is difficult to conduct long-term follow-up and biochemical evaluation in humans. In this study, we detected the effect of oocyte vitrification on gene expression in the organs of adult mice offspring by RNA sequencing for the first time. Our results showed that only a small amount of gene expression was significantly affected. Seven genes (Tpm3, Hspe1-rs1, Ntrk2, Cyp4a31, Asic5, Cyp4a14, Retsat) were abnormally expressed in the liver, and ten genes (Lbp, Hspe1-rs1, Prxl2b, Pfn3, Gm9008, Bglap3, Col8a1, Hmgcr, Ero1lb, Ifi44l) were abnormal in the kidney. Several genes were related to metabolism and disease occurrence in the liver or kidney. Besides, we paid special attention to the expression of known imprinted genes and DNA methylation-related genes in adult organs, which are susceptible to oocyte cryopreservation in the preimplantation stage. As a result, some of these transcripts were detected in adult organs, but they were not affected by oocyte vitrification. In conclusion, we first report that oocyte vitrification did not significantly change the global gene expression in offspring organs; nonetheless, it can still influence the transcription of a few functional genes. The potential adverse effects caused by oocyte vitrification need attention and further study.

DNA methylation regulator-mediated modification patterns and tumor microenvironment characterization in glioma.

Growing evidences indicate DNA methylation plays a crucial regulatory role in inflammation, innate immunity, and immunotherapy. However, the overall landscape of various DNA methylation regulatory genes and their relationship with the infiltration of immune cells into the tumor microenvironment (TME) as well as the response to immunotherapy in gliomas is still not clear. Therefore, we comprehensively analyzed the correlation between DNA methylation regulator patterns, infiltration of immune cell-types, and tumor immune response status in gather glioma cohorts. Furthermore, we calculated the DNA methylation score (DMS) for individual glioma samples, then evaluated the relationship between DMS, clinicopathological characteristics, and overall survival (OS) in patients with gliomas. Our results showed three distinct DNA methylation regulator patterns among the glioma patients which correlated with three distinct tumor immune response phenotypes, namely, immune-inflamed, immune-excluded, and immune desert. We then calculated DMS for individual glioma samples based on the expression of DNA methylation-related gene clusters. Furthermore, DMS, tumor mutation burden (TMB), programmed death 1 (PD-1) expression, immune cell infiltration status in the TME, and Tumor Immune Dysfunction and Exclusion (TIDE) scores were associated with survival outcomes and clinical responses to immune checkpoint blockade therapy. We also validated the predictive value of DMS in two independent immunotherapy cohorts. In conclusion, our results demonstrated that three DNA methylation regulator patterns that correlated with three tumor immune response phenotypes. Moreover, we demonstrated that DMS was an independent predictive biomarker that correlated with survival outcomes of glioma patients and their responses to immunotherapy therapeutic regimens.

Selected Articles from This Issue

Inflammatory and insulinemic pathways have been linked to prostate cancer; thus, health behaviors that activate these pathways may impact prostate cancer survivorship. In this study, Langlais and colleagues predicted biomarker levels of inflammation, hyperinsulinemia, and insulin resistance pathways from questionnaire data among 2,056 men with prostate cancer. The authors examined the scores in relation to risk of prostate cancer progression. Over a median of 6.4 years of follow-up, the most pro-inflammatory and pro-insulinemic behaviors following a prostate cancer diagnosis were associated with a 1.6- to 2.8-fold increased risk of prostate cancer progression. Limiting inflammation and insulin hypersecretion through diet and physical activity may improve prostate cancer survivorship.Testicular germ cell tumors (TGCTs), whose etiology is largely unknown, are believed to arise from primordial gonocytes with an altered DNA methylation reprogramming. Grasso and colleagues evaluated the association between 273 single-nucleotide polymorphisms (SNPs) from 28 DNA methylation-related genes and TGCT risk using summary statistics from the Genome Wide Association Study meta-analysis of the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. Four MTHFR SNPs, potentially affecting DNA methylation pattern, were associated with TGCT risk. This suggests that TGCT pathogenesis could be linked to folate cycle status, and this relation could be partly due to hereditary factors.In the United States (US), the incidence of Hodgkin lymphoma (HL) differs by ethnicity. In a large population-based case-control study, Graham and colleagues found that having a foreign-born mother (versus a US-born mother) was associated with an increased risk of early onset HL among non-Hispanic White individuals and a decreased risk among Hispanic individuals. In addition, sex, birthweight and parental age were also linked to risk of early onset HL. The findings suggest that the etiology of early onset HL is multi-faceted, and the observed disparity warrants further evaluation.This article describes the randomized transition from established cytology-based screening to primary HPV-based screening in Norway. This programmatic change required substantial modifications to existing infrastructure and screening protocols, affecting activity volumes, staff training, and changes in the data-flow and communication systems. Nygård and colleagues report a relative increase of 60% in the detection of cervical precancers and 40% in cancer using HPV-based screening as compared to the cytology-based screening. Introducing new screening technology gradually and in a controlled manner should be considered in both established and novel population-based cancer screening programs and specifically implementing HPV-based screening to advance the cervical cancer elimination.

Identification of Prognostic DNA Methylation Signatures in Lung Adenocarcinoma.

Background Increasing evidence exists of a link between DNA methylation and tumor immunotherapy. However, the impact of DNA methylation on the characteristics of the lung adenocarcinoma microenvironment and its effect on immunotherapy remain unclear. Method This study collected TCGA-LUAD related data sets (LUAD) to explore the characteristics and regulation of 20 DNA methylation-related genes. We further identified two DNA methylation subtypes by analysing the expression profiles of these 20 DNA methylation-related genes. Subsequently, the differences in immune cell infiltration (ICI) and the expression of immune-related signaling factors among different DNA methylation subtypes were explored, and the differentially expressed genes (DEGs) among different LUAD DNA methylation subtypes were identified. Using univariate Cox to screen differentially expressed genes meaningful for survival, a DNA methylation score (DMS) was constructed based on the weight of the first and second dimensions after dimensionality reduction by principal component analysis (PCA). Our study found that DMS can better evaluate the prognosis of lung adenocarcinoma. Results Based on DMS, LUAD samples were divided into two groups with high and low scores. The differences in clinical characteristics, tumor mutation load, and tumor immune cell infiltration between different DMS groups of LUAD were deeply explored, and the prediction ability of DMS for the benefit of immunotherapy was evaluated. Conclusions DMS is a valuable tool for predicting survival, clinicopathological features, and immunotherapeutic efficacy, which may help to promote personalized LUAD immunotherapy in the future.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

RecQ mediated genome instability 2 (RMI2): a potential prognostic and immunological biomarker for pan-cancers.

Background: RecQ mediated genome instability 2 (RMI2) is an essential component of the BLM-TopoIIIa-RMI1-RMI2 (BTR) complex. However, the mysterious veil of the potential immunological relationship of RMI2 in tumorigenesis and development has not been revealed.Methods: We conducted the differential expression (DE) analysis of the RMI2 in pan-cancer using data onto Oncomine, TIMER, and GEPIA databases. Afterward, survival analysis and clinical-stage correlation analysis were performed via the TCGA database. Subsequently, we used R software to further explore the relationship between the expression level of RMI2 and tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), tumor immune-infiltrated cells (TILs), immune checkpoints (ICP), mismatch repairs (MMRs) -related genes, m6A-related genes, DNA methylation-related genes. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional networks were also performed for annotation via gene set enrichment analysis (GSEA).Results: The RMI2 expressed remarkably high in most cancer types compared to cancer adjacent normal tissues (P < 0.05). High expression of RMI2 was linked to unfavorable prognosis and advanced stage of disease, especially in LIHC and PAAD. RMI2 expression was related to TMB in 16 cancer types and MSI in 8 cancer types. Furthermore, it is significant positive correlations between RMI2 and stromal and immune cells, ICP-related genes, MMRs-related genes, m6A-related genes, and DNA methylation-related genes. Finally, GSEA analysis revealed that RMI2 was engaged in a variety of signaling pathways in pan-cancers.Conclusions: RMI2 may serve as a potential biological target and probably assume a crucial part in tumorigenesis and progression.