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Cells Jun 2024The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but... (Review)
Review
The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.
Topics: Amyotrophic Lateral Sclerosis; Humans; Epigenesis, Genetic; DNA Methylation; Carbon; Animals
PubMed: 38891099
DOI: 10.3390/cells13110967 -
Journal of Hematology & Oncology Jun 2024Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in...
Non-invasive diagnosis of esophageal cancer by a simplified circulating cell-free DNA methylation assay targeting OTOP2 and KCNA3: a double-blinded, multicenter, prospective study.
BACKGROUND
Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in circulating cell-free DNA from patients with EC. We then developed a blood-based methylation assay targeting OTOP2 and KCNA3 (named "IEsohunter") for esophageal cancer noninvasive detection. This double-blinded, multicenter, prospective study aimed to comprehensively evaluate its clinical diagnostic performance.
METHODS
Participants with EC, high-grade intraepithelial neoplasia (HGIN), other malignancies, benign gastrointestinal lesions, or no abnormalities were prospectively enrolled from 5 tertiary referral centers across China. Peripheral blood samples were collected, followed by plasma cell-free DNA methylation analysis using the IEsohunter test based on multiplex quantitative polymerase chain reaction adopting an algorithm-free interpretation strategy. The primary outcome was the diagnostic accuracy of IEsohunter test for EC.
RESULTS
We prospectively enrolled 1116 participants, including 334 patients with EC, 71 with HGIN, and 711 controls. The areas under the receiver operating characteristic curves of the IEsohunter test for detecting EC and HGIN were 0.903 (95% CI 0.880-0.927) and 0.727 (95% CI 0.653-0.801), respectively. IEsohunter test showed sensitivities of 78.5% (95% CI 69.1-85.6), 87.3% (95% CI 79.4-92.4), 92.5% (95% CI 85.9-96.2), and 96.9% (95% CI 84.3-99.8) for stage I-IV EC, respectively, with an overall sensitivity of 87.4% (95% CI 83.4-90.6) and specificity of 93.3% (95% CI 91.2-94.9) for EC detection. The IEsohunter test status turned negative (100.0%, 47/47) after surgical resection of EC.
CONCLUSIONS
The IEsohunter test showed high diagnostic accuracy for EC detection, indicating that it could potentially serve as a tool for noninvasive early detection and surveillance of EC.
Topics: Humans; Esophageal Neoplasms; Male; Female; Prospective Studies; Middle Aged; DNA Methylation; Double-Blind Method; Aged; Biomarkers, Tumor; Cell-Free Nucleic Acids; Adult
PubMed: 38890756
DOI: 10.1186/s13045-024-01565-2 -
European Journal of Medical Research Jun 2024Synaptotagmin 11 (SYT11) plays a pivotal role in neuronal vesicular trafficking and exocytosis. However, no independent prognostic studies have focused on various...
BACKGROUND
Synaptotagmin 11 (SYT11) plays a pivotal role in neuronal vesicular trafficking and exocytosis. However, no independent prognostic studies have focused on various cancers. In this study, we aimed to summarize the clinical significance and molecular landscape of SYT11 in various tumor types.
METHODS
Using several available public databases, we investigated abnormal SYT11 expression in different tumor types and its potential clinical association with prognosis, methylation profiling, immune infiltration, gene enrichment analysis, and protein-protein interaction analysis, and identified common pathways.
RESULTS
TCGA and Genotype-Tissue Expression (GTEx) showed that SYT11 was widely expressed across tumor and corresponding normal tissues. Survival analysis showed that SYT11 expression correlated with the prognosis of seven cancer types. Additionally, SYT11 mRNA expression was not affected by promoter methylation, but regulated by certain miRNAs and associated with cancer patient prognosis. In vitro experiments further verified a negative correlation between the expression of SYT11 and miR-19a-3p in human colorectal, lung, and renal cancer cell lines. Moreover, aberrant SYT11 expression was significantly associated with immune infiltration. Pathway enrichment analysis revealed that the biological and molecular processes of SYT11 were related to clathrin-mediated endocytosis, Rho GTPase signaling, and cell motility-related functions.
CONCLUSIONS
Our results provide a clear understanding of the role of SYT11 in various cancer types and suggest that SYT11 may be of prognostic and clinical significance.
Topics: Humans; Biomarkers, Tumor; Cell Line, Tumor; DNA Methylation; Gene Expression Regulation, Neoplastic; MicroRNAs; Neoplasms; Prognosis; Synaptotagmins
PubMed: 38890718
DOI: 10.1186/s40001-024-01931-3 -
Clinical Epigenetics Jun 2024Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. Studies have indicated that estrogen can regulate the expression of miRNAs in numerous malignancies....
BACKGROUND
Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. Studies have indicated that estrogen can regulate the expression of miRNAs in numerous malignancies. MiR-570-3p has been shown to have a regulatory function in various cancers. However, studies of the regulatory function of miR-570-3p and a direct link between estrogen (especially estradiol E2) and miR-570-3p in PTC have not been done.
METHODS
Expression of miR-570-3p and its downstream target DPP4 in PTC tissues and cells was predicted using bioinformatics and validated by qRT-PCR and western blot assays. We then performed a series of gain-and-loss experiments to assess the functional significance of miR-570-3p/DPP4 axis in PTC progression in vitro and in vivo. Additionally, the methylation of the miR-570-3p promoter region was examined via bioinformatics analysis and MSP. Finally, the effects of E2 on PTC progression and the correlation between DNMT1/DNMT3A and EZH2 were predicted by bioinformatic tools and proved by luciferase reporter, ChIP, and co-IP assays.
RESULTS
In PTC tumor tissues and cell lines, there was a lower expression level and a higher methylation level of miR-570-3p compared to normal tissues and cell lines. DPP4 was identified as the downstream target of miR-570-3p. Overexpression of miR-570-3p reduced the proliferative, migratory, and invasive capabilities, and promoted apoptosis, while overexpression of DPP4 reversed these effects in PTC cells. It was also discovered that DNMT1 and DNMT3A increased the CpG methylation level of the miR-570-3p promoter in an EZH2-dependent manner, which led to decreased expression of miR-570-3p. Furthermore, we observed that estrogen (E2) enhanced the methylation of miR-570-3p and suppressed its expression levels, resulting in augmented tumor growth in vivo in PTC.
CONCLUSION
Estrogen regulates the EZH2/DNMTs/miR-570-3p/DPP4 signaling pathway to promote PTC progression.
Topics: Humans; MicroRNAs; DNA (Cytosine-5-)-Methyltransferase 1; Enhancer of Zeste Homolog 2 Protein; Thyroid Cancer, Papillary; Dipeptidyl Peptidase 4; DNA Methyltransferase 3A; Cell Line, Tumor; Thyroid Neoplasms; Estrogens; Gene Expression Regulation, Neoplastic; Female; Mice; DNA Methylation; Animals; DNA (Cytosine-5-)-Methyltransferases; Cell Proliferation; Male; Promoter Regions, Genetic
PubMed: 38890707
DOI: 10.1186/s13148-024-01685-z -
BMC Cancer Jun 2024Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical...
BACKGROUND
Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical trials. A better understanding of the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia is needed for future clinical application. Here, we investigated the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia in patients with localized PCa, in order to apply PIMO as a prognostic tool and to identify potential biomarkers for future clinical translation.
METHODS
A total of 39 patients with localized PCa were recruited and administered oral PIMO before undergoing radical prostatectomy (RadP). Immunohistochemical staining for PIMO was performed on 37 prostatectomy specimens with staining patterns evaluated and clinical association analyzed. Whole genome bisulfite sequencing was performed using laser-capture of microdissected specimen sections comparing PIMO positive and negative tumor areas. A hypoxia related methylation molecular signature was generated by integrating the differentially methylated regions with previously established RNA-seq datasets.
RESULTS
Three PIMO staining patterns were distinguished: diffuse, focal, and comedo-like. The comedo-like staining pattern was more commonly associated with adverse pathology. PIMO-defined hypoxia intensity was positively correlated with advanced pathologic stage, tumor invasion, and cribriform and intraductal carcinoma morphology. The generated DNA methylation signature was found to be a robust hypoxia biomarker, which could risk-stratify PCa patients across multiple clinical datasets, as well as be applicable in other cancer types.
CONCLUSIONS
Oral PIMO unveiled clinicopathologic features of disease aggressiveness in localized PCa. The generated DNA methylation signature is a novel and robust hypoxia biomarker that has the potential for future clinical translation.
Topics: Humans; Male; Prostatic Neoplasms; Aged; Middle Aged; Epigenesis, Genetic; Prostatectomy; DNA Methylation; Nitroimidazoles; Tumor Hypoxia; Biomarkers, Tumor; Prognosis; Administration, Oral
PubMed: 38890593
DOI: 10.1186/s12885-024-12505-1 -
Scientific Reports Jun 2024Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It is...
Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It is characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematological malignancies. Although FPDMM is a precursor for diseases involving abnormal DNA methylation, the DNA methylation status in FPDMM remains unknown, largely due to a lack of animal models and challenges in obtaining patient-derived samples. Here, using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous RUNX1 mutations. These iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. The FPDMM-mimicking HPCs showed DNA methylation patterns distinct from those of wild-type HPCs, with hypermethylated regions showing the enrichment of ETS transcription factor (TF) motifs. We found that the expression of FLI1, an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a RUNX1 transactivation domain (TAD) mutation. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of FLI1 restored their megakaryocytic differentiation efficiency and hypermethylation status. These findings suggest that FLI1 plays a crucial role in regulating DNA methylation and correcting defective megakaryocytic differentiation in FPDMM-mimicking HPCs with a RUNX1 TAD mutation.
Topics: Core Binding Factor Alpha 2 Subunit; Humans; DNA Methylation; Megakaryocytes; Proto-Oncogene Protein c-fli-1; Cell Differentiation; Induced Pluripotent Stem Cells; Mutation; Blood Platelet Disorders; Transcriptional Activation; Hematopoietic Stem Cells; Leukemia, Myeloid, Acute; Blood Coagulation Disorders, Inherited
PubMed: 38890442
DOI: 10.1038/s41598-024-64829-4 -
Genome Biology Jun 2024Lettuce (Lactuca sativa L.) is an economically important vegetable crop worldwide. Lettuce is believed to be domesticated from a single wild ancestor Lactuca serriola...
BACKGROUND
Lettuce (Lactuca sativa L.) is an economically important vegetable crop worldwide. Lettuce is believed to be domesticated from a single wild ancestor Lactuca serriola and subsequently diverged into two major morphologically distinct vegetable types: leafy lettuce and stem lettuce. However, the role of epigenetic variation in lettuce domestication and divergence remains largely unknown.
RESULTS
To understand the genetic and epigenetic basis underlying lettuce domestication and divergence, we generate single-base resolution DNA methylomes from 52 Lactuca accessions, including major lettuce cultivars and wild relatives. We find a significant increase of DNA methylation during lettuce domestication and uncover abundant epigenetic variations associated with lettuce domestication and divergence. Interestingly, DNA methylation variations specifically associated with leafy and stem lettuce are related to regulation and metabolic processes, respectively, while those associated with both types are enriched in stress responses. Moreover, we reveal that domestication-induced DNA methylation changes could influence expression levels of nearby and distal genes possibly through affecting chromatin accessibility and chromatin loop.
CONCLUSION
Our study provides population epigenomic insights into crop domestication and divergence and valuable resources for further domestication for diversity and epigenetic breeding to boost crop improvement.
Topics: Lactuca; DNA Methylation; Domestication; Epigenesis, Genetic; Genetic Variation; Crops, Agricultural; Gene Expression Regulation, Plant; Genome, Plant
PubMed: 38886807
DOI: 10.1186/s13059-024-03310-x -
BMC Pregnancy and Childbirth Jun 2024Pregnancy induced hypertension (PIH) syndrome is a disease that unique to pregnant women and is associated with elevated risk of offspring cardiovascular diseases (CVDs)...
OBJECTIVIES
Pregnancy induced hypertension (PIH) syndrome is a disease that unique to pregnant women and is associated with elevated risk of offspring cardiovascular diseases (CVDs) and neurodevelopmental disorders in their kids. Previous research on cord blood utilizing the Human Methylation BeadChip or EPIC array revealed that PIH is associated with specific DNA methylation site. Here, we investigate the whole genome DNA methylation landscape of cord blood from newborns of PIH mother.
METHODS
Whole-genome bisulfite sequencing (WGBS) was used to examine the changes in whole genome DNA methylation in the umbilical cord blood of three healthy (NC) and four PIH individuals. Using methylKit, we discovered Hypo- and hyper- differentially methylated probes (DMPs) or methylated regions (DMRs) in the PIH patients' cord blood DNA. Pathway enrichments were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays. DMPs or DMRs relevant to the immunological, neurological, and circulatory systems were also employed for enrichment assay, Metascape analysis and PPI network analysis.
RESULTS
520 hyper- and 224 hypo-DMPs, and 374 hyper- and 186 hypo-DMRs between NC and PIH group, respectively. Both DMPs and DMRs have enhanced pathways for cardiovascular, neurological system, and immune system development. Further investigation of DMPs or DMRs related to immunological, neurological, and circulatory system development revealed that TBK1 served as a hub gene for all three developmental pathways.
CONCLUSION
PIH-associated DMPs or DMRs in umbilical cord blood DNA may play a role in immunological, neurological, and circulatory system development. Abnormal DNA methylation in the immune system may also contribute to the development of CVDs and neurodevelopment disorders.
Topics: Humans; DNA Methylation; Female; Pregnancy; Fetal Blood; Infant, Newborn; Hypertension, Pregnancy-Induced; Adult; Epigenome; Epigenesis, Genetic; Case-Control Studies; Whole Genome Sequencing
PubMed: 38886689
DOI: 10.1186/s12884-024-06623-8 -
BMC Genomics Jun 2024Spermatogenesis is a highly regulated and complex process in which DNA methylation plays a crucial role. This study aimed to explore the differential methylation...
BACKGROUND
Spermatogenesis is a highly regulated and complex process in which DNA methylation plays a crucial role. This study aimed to explore the differential methylation profiles in sperm DNA between patients with asthenospermia (AS) and healthy controls (HCs), those with oligoasthenospermia (OAS) and HCs, and patients with AS and those with OAS.
RESULTS
Semen samples and clinical data were collected from five patients with AS, five patients with OAS, and six age-matched HCs. Reduced representation bisulfite sequencing (RRBS) was performed to identify differentially methylated regions (DMRs) in sperm cells among the different types of patients and HCs. A total of 6520, 28,019, and 16,432 DMRs were detected between AS and HC, OAS and HC, and AS and OAS groups, respectively. These DMRs were predominantly located within gene bodies and mapped to 2868, 9296, and 9090 genes in the respective groups. Of note, 12, 9, and 8 DMRs in each group were closely associated with spermatogenesis and male infertility. Furthermore, BDNF, SMARCB1, PIK3CA, and DDX27; RBMX and SPATA17; ASZ1, CDH1, and CHDH were identified as strong differentially methylated candidate genes in each group, respectively. Meanwhile, the GO analysis of DMR-associated genes in the AS vs. HC groups revealed that protein binding, cytoplasm, and transcription (DNA-templated) were the most enriched terms in the biological process (BP), cellular component (CC), and molecular function (MF), respectively. Likewise, in both the OAS vs. HC and AS vs. OAS groups, GO analysis revealed protein binding, nucleus, and transcription (DNA-templated) as the most enriched terms in BP, CC, and MF, respectively. Finally, the KEGG analysis of DMR-annotated genes and these genes at promoters suggested that metabolic pathways were the most significantly associated across all three groups.
CONCLUSIONS
The current study results revealed distinctive sperm DNA methylation patterns in the AS vs. HC and OAS vs. HC groups, particularly between patients with AS and those with OAS. The identification of key genes associated with spermatogenesis and male infertility in addition to the differentially enriched metabolic pathways may contribute to uncovering the potential pathogenesis in different types of abnormal sperm parameters.
Topics: Humans; DNA Methylation; Male; Asthenozoospermia; Adult; Oligospermia; Spermatozoa; Spermatogenesis; Case-Control Studies; Epigenesis, Genetic
PubMed: 38886667
DOI: 10.1186/s12864-024-10491-z -
BMC Plant Biology Jun 2024Wild emmer wheat is a great candidate to revitalize domesticated wheat genetic diversity. Recent years have seen intensive investigation into the evolution and...
BACKGROUND
Wild emmer wheat is a great candidate to revitalize domesticated wheat genetic diversity. Recent years have seen intensive investigation into the evolution and domestication of wild emmer wheat, including whole-genome DNA and transcriptome sequencing. However, the impact of intraspecific hybridization on the transcriptome of wild emmer wheat has been poorly studied. In this study, we assessed changes in methylation patterns and transcriptomic variations in two accessions of wild emmer wheat collected from two marginal populations, Mt. Hermon and Mt. Amasa, and in their stable F4 hybrid.
RESULTS
Methylation-Sensitive Amplified Polymorphism (MSAP) detected significant cytosine demethylation in F4 hybrids vs. parental lines, suggesting potential transcriptome variation. After a detailed analysis, we examined nine RNA-Seq samples, which included three biological replicates from the F4 hybrid and its parental lines. RNA-Seq databases contained approximately 200 million reads, with each library consisting of 15 to 25 million reads. There are a total of 62,490 well-annotated genes in these databases, with 6,602 genes showing differential expression between F4 hybrid and parental lines Mt. Hermon and Mt. Amasa. The differentially expressed genes were classified into four main categories based on their expression patterns. Gene ontology (GO) analysis revealed that differentially expressed genes are associated with DNA/RNA metabolism, photosynthesis, stress response, phosphorylation and developmental processes.
CONCLUSION
This study highlights the significant transcriptomic changes resulting from intraspecific hybridization within natural plant populations, which might aid the nascent hybrid in adapting to various environmental conditions.
Topics: Triticum; Transcriptome; Hybridization, Genetic; DNA Methylation; Genetic Variation
PubMed: 38886665
DOI: 10.1186/s12870-024-05258-3