Anne K Bozack, Sheryl L Rifas-Shiman, Diane R Gold, Zachary M Laubach, Wei Perng, Marie-France Hivert, Andres Cardenas
{"title":"DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort.","authors":"Anne K Bozack, Sheryl L Rifas-Shiman, Diane R Gold, Zachary M Laubach, Wei Perng, Marie-France Hivert, Andres Cardenas","doi":"10.1186/s13148-023-01480-2","DOIUrl":"10.1186/s13148-023-01480-2","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA.</p><p><strong>Results: </strong>Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA r = 0.82, p < 0.001). Horvath and skin & blood EA were weakly correlated with gestational age, but moderately correlated with chronological age in childhood (r = 0.45-0.65). Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males. When comparing self-reported Asian, Black, Hispanic, and more than one race or other racial/ethnic groups to White, we identified significant differences in EGAA and EAA at birth and in mid-childhood, but associations varied across clocks. Horvath EA at birth was positively associated with childhood Horvath and skin & blood EAA.</p><p><strong>Conclusions: </strong>Maternal smoking during pregnancy and child sex were associated with EGAA and EAA at multiple timepoints. Further research may provide insight into the relationship between perinatal factors, pediatric epigenetic aging, and health and development across the lifespan.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"62"},"PeriodicalIF":5.7,"publicationDate":"2023-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9706359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yang Pan, Xiao Sun, Zhijie Huang, Ruiyuan Zhang, Changwei Li, Amanda H Anderson, James P Lash, Tanika N Kelly
{"title":"Effects of epigenetic age acceleration on kidney function: a Mendelian randomization study.","authors":"Yang Pan, Xiao Sun, Zhijie Huang, Ruiyuan Zhang, Changwei Li, Amanda H Anderson, James P Lash, Tanika N Kelly","doi":"10.1186/s13148-023-01476-y","DOIUrl":"https://doi.org/10.1186/s13148-023-01476-y","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function.</p><p><strong>Results: </strong>Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR.</p><p><strong>Conclusion: </strong>This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"61"},"PeriodicalIF":5.7,"publicationDate":"2023-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9367649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joana B Serrano, Nils C Tabeling, Cindy M de Winter-Korver, Saskia K M van Daalen, Ans M M van Pelt, Callista L Mulder
{"title":"Sperm DNA methylation is predominantly stable in mice offspring born after transplantation of long-term cultured spermatogonial stem cells.","authors":"Joana B Serrano, Nils C Tabeling, Cindy M de Winter-Korver, Saskia K M van Daalen, Ans M M van Pelt, Callista L Mulder","doi":"10.1186/s13148-023-01469-x","DOIUrl":"https://doi.org/10.1186/s13148-023-01469-x","url":null,"abstract":"<p><strong>Background: </strong>Spermatogonial stem cell transplantation (SSCT) is proposed as a fertility therapy for childhood cancer survivors. SSCT starts with cryopreserving a testicular biopsy prior to gonadotoxic treatments such as cancer treatments. When the childhood cancer survivor reaches adulthood and desires biological children, the biopsy is thawed and SSCs are propagated in vitro and subsequently auto-transplanted back into their testis. However, culturing stress during long-term propagation can result in epigenetic changes in the SSCs, such as DNA methylation alterations, and might be inherited by future generations born after SSCT. Therefore, SSCT requires a detailed preclinical epigenetic assessment of the derived offspring before this novel cell therapy is clinically implemented. With this aim, the DNA methylation status of sperm from SSCT-derived offspring, with in vitro propagated SSCs, was investigated in a multi-generational mouse model using reduced-representation bisulfite sequencing.</p><p><strong>Results: </strong>Although there were some methylation differences, they represent less than 0.5% of the total CpGs and methylated regions, in all generations. Unsupervised clustering of all samples showed no distinct grouping based on their pattern of methylation differences. After selecting the few single genes that are significantly altered in multiple generations of SSCT offspring compared to control, we validated the results with quantitative Bisulfite Sanger sequencing and RT-qPCRin various organs. Differential methylation was confirmed only for Tal2, being hypomethylated in sperm of SSCT offspring and presenting higher gene expression in ovaries of SSCT F1 offspring compared to control F1.</p><p><strong>Conclusions: </strong>We found no major differences in DNA methylation between SSCT-derived offspring and control, both in F1 and F2 sperm. The reassuring outcomes from our study are a prerequisite for promising translation of SSCT to the human situation.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"58"},"PeriodicalIF":5.7,"publicationDate":"2023-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yili Ping, Jingjuan Huang, Jichao Zhu, Zujun Sun, Anquan Shang, Chen Chen, Wenfang Liu, Dong Li
{"title":"Comprehensive analyses of molecular features, prognostic values, and regulatory functionalities of m<sup>6</sup>A-modified long non-coding RNAs in lung adenocarcinoma.","authors":"Yili Ping, Jingjuan Huang, Jichao Zhu, Zujun Sun, Anquan Shang, Chen Chen, Wenfang Liu, Dong Li","doi":"10.1186/s13148-023-01475-z","DOIUrl":"https://doi.org/10.1186/s13148-023-01475-z","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) has a high incidence and recurrence rate. N6-methyladenosine (m<sup>6</sup>A) modification of RNA has become a promising epigenetic marker in tumors. The dysregulation of both RNA m<sup>6</sup>A levels and m<sup>6</sup>A regulator expression levels reportedly affects essential biological processes in various tumors. Long non-coding RNAs (lncRNAs), a subgroup of RNAs over 200 nucleotides in length that do not code for protein, can be modified and regulated by m<sup>6</sup>A, but the relevant profile in LUAD remains unclear.</p><p><strong>Results: </strong>The m<sup>6</sup>A levels of total RNA were decreased in LUAD tumor tissues and cells. Multiple m<sup>6</sup>A regulators were abnormally expressed at both the RNA and protein levels, and were related in expression patterns and functionally synergistic. Our microarray revealed 2846 m<sup>6</sup>A-modified lncRNA transcripts as well as its molecular features, 143 of which were differentially m<sup>6</sup>A-modified and manifested a negative correlation between expression levels and m<sup>6</sup>A modification levels. More than half of the differentially m<sup>6</sup>A-modified lncRNAs associated with dysregulated expression. The 6-MRlncRNA risk signature was a reliable indicator for assessing survival time of LUAD patients. The competitive endogenous regulatory network suggested a potential m<sup>6</sup>A-induced pathogenicity in LUAD.</p><p><strong>Conclusions: </strong>These data have demonstrated that differential RNA m<sup>6</sup>A modification and m<sup>6</sup>A regulator expression levels were identified in LUAD patients. In addition, this study provides evidence increasing the understanding of molecular features, prognostic values, and regulatory functionalities of m<sup>6</sup>A-modified lncRNAs in LUAD.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"60"},"PeriodicalIF":5.7,"publicationDate":"2023-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9737442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guoying Wang, Richard Xu, Boyang Zhang, Xiumei Hong, Tami R Bartell, Colleen Pearson, Liming Liang, Xiaobin Wang
{"title":"Impact of intrauterine exposure to maternal diabetes on preterm birth: fetal DNA methylation alteration is an important mediator.","authors":"Guoying Wang, Richard Xu, Boyang Zhang, Xiumei Hong, Tami R Bartell, Colleen Pearson, Liming Liang, Xiaobin Wang","doi":"10.1186/s13148-023-01473-1","DOIUrl":"https://doi.org/10.1186/s13148-023-01473-1","url":null,"abstract":"<p><strong>Background: </strong>In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population.</p><p><strong>Methods: </strong>This study included 954 mother-newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package.</p><p><strong>Results: </strong>126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%.</p><p><strong>Conclusions: </strong>In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"59"},"PeriodicalIF":5.7,"publicationDate":"2023-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qin Xiang, Dishu Zhou, Xinni Xiang, Xin Le, Chaoqun Deng, Ran Sun, Chunhong Li, Huayang Pang, Jin He, Zeze Zheng, Jun Tang, Weiyan Peng, Xi Peng, Xiaoqian He, Fan Wu, Jingfu Qiu, Yongzhu Xu, Tingxiu Xiang
{"title":"Neuroglobin plays as tumor suppressor by disrupting the stability of GPR35 in colorectal cancer.","authors":"Qin Xiang, Dishu Zhou, Xinni Xiang, Xin Le, Chaoqun Deng, Ran Sun, Chunhong Li, Huayang Pang, Jin He, Zeze Zheng, Jun Tang, Weiyan Peng, Xi Peng, Xiaoqian He, Fan Wu, Jingfu Qiu, Yongzhu Xu, Tingxiu Xiang","doi":"10.1186/s13148-023-01472-2","DOIUrl":"https://doi.org/10.1186/s13148-023-01472-2","url":null,"abstract":"<p><strong>Background: </strong>The incidence of colorectal cancer (CRC) has increased in recent years. Identification of accurate tumor markers has become the focus of CRC research. Early and frequent DNA methylation tends to occur in cancer. Thus, identifying accurate methylation biomarkers would improve the efficacy of CRC treatment. Neuroglobin (NGB) is involved in neurological and oncological diseases. However, there are currently no reports on epigenetic regulation involvement of NGB in CRC.</p><p><strong>Results: </strong>NGB was downregulated or silenced in majority CRC tissues and cell lines. The hypermethylation of NGB was detected in tumor tissue, but no or a very low methylation frequency in normal tissues. Overexpression of NGB induced G2/M phase arrest and apoptosis, suppressed proliferation, migration, invasion in vitro, and inhibited CRC tumor growth and angiogenesis in vivo. Isobaric tag for relative and absolute quantitation (Itraq)-based proteomics identified approximately 40% proteins related to cell-cell adhesion, invasion, and tumor vessel formation in the tumor microenvironment, among which GPR35 was proved critical for NGB-regulated tumor angiogenesis suppression in CRC.</p><p><strong>Conclusions: </strong>NGB, an epigenetically silenced factor, inhibits metastasis through the GPR35 in CRC. It is expected to grow into a potential cancer risk assessment factor and a valuable biomarker for early diagnosis and prognosis assessment of CRC.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"57"},"PeriodicalIF":5.7,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hela Koka, Clara Bodelon, Steve Horvath, Priscilla Ming Yi Lee, Difei Wang, Lei Song, Tongwu Zhang, Amber N Hurson, Jennifer Lyn Guida, Bin Zhu, Maeve Bailey-Whyte, Feng Wang, Cherry Wu, Koon Ho Tsang, Yee-Kei Tsoi, W C Chan, Sze Hong Law, Ray Ka Wai Hung, Gary M Tse, Karen Ka-Wan Yuen, Eric Karlins, Kristine Jones, Aurelie Vogt, Bin Zhu, Amy Hutchinson, Belynda Hicks, Montserrat Garcia-Closas, Stephen Chanock, Jill Barnholtz-Sloan, Lap Ah Tse, Xiaohong R Yang
{"title":"DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer.","authors":"Hela Koka, Clara Bodelon, Steve Horvath, Priscilla Ming Yi Lee, Difei Wang, Lei Song, Tongwu Zhang, Amber N Hurson, Jennifer Lyn Guida, Bin Zhu, Maeve Bailey-Whyte, Feng Wang, Cherry Wu, Koon Ho Tsang, Yee-Kei Tsoi, W C Chan, Sze Hong Law, Ray Ka Wai Hung, Gary M Tse, Karen Ka-Wan Yuen, Eric Karlins, Kristine Jones, Aurelie Vogt, Bin Zhu, Amy Hutchinson, Belynda Hicks, Montserrat Garcia-Closas, Stephen Chanock, Jill Barnholtz-Sloan, Lap Ah Tse, Xiaohong R Yang","doi":"10.1186/s13148-023-01465-1","DOIUrl":"https://doi.org/10.1186/s13148-023-01465-1","url":null,"abstract":"<p><strong>Background: </strong>Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong.</p><p><strong>Methods: </strong>We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath's pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson's correlation (r), Kruskal-Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors.</p><p><strong>Results: </strong>DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e-16) than in tumor tissue (Pearson r = 0.31, P = 7.8e-06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e-06) and PGR (Pearson r = 0.36, P = 2.4e-05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA.</p><p><strong>Conclusions: </strong>Our findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"55"},"PeriodicalIF":5.7,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mykhailo Krolevets, Vincent Ten Cate, Jürgen H Prochaska, Andreas Schulz, Steffen Rapp, Stefan Tenzer, Miguel A Andrade-Navarro, Steve Horvath, Christof Niehrs, Philipp S Wild
{"title":"DNA methylation and cardiovascular disease in humans: a systematic review and database of known CpG methylation sites.","authors":"Mykhailo Krolevets, Vincent Ten Cate, Jürgen H Prochaska, Andreas Schulz, Steffen Rapp, Stefan Tenzer, Miguel A Andrade-Navarro, Steve Horvath, Christof Niehrs, Philipp S Wild","doi":"10.1186/s13148-023-01468-y","DOIUrl":"https://doi.org/10.1186/s13148-023-01468-y","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking.</p><p><strong>Results: </strong>A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function \"DNA-binding transcription activator activity\" (q = 1.65 × 10<sup>-11</sup>) and biological processes \"skeletal system development\" (q = 1.89 × 10<sup>-23</sup>). Gene enrichment demonstrated that general CVD-related terms are shared, while \"heart\" and \"vasculature\" specific genes have more disease-specific terms as PR interval for \"heart\" or platelet distribution width for \"vasculature.\" STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10<sup>-6</sup>) and atherosclerosis (p = 4.9 × 10<sup>-4</sup>).</p><p><strong>Conclusion: </strong>This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"56"},"PeriodicalIF":5.7,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical characteristics and prognostic significance of DNA methylation regulatory gene mutations in acute myeloid leukemia.","authors":"Xiaoyan Xu, Hong Wang, Haohao Han, Yifang Yao, Xueqian Li, Jiaqian Qi, Chengsen Cai, Meng Zhou, Yaqiong Tang, Tingting Pan, Ziyan Zhang, Jingyi Yang, Depei Wu, Yue Han","doi":"10.1186/s13148-023-01474-0","DOIUrl":"10.1186/s13148-023-01474-0","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation is a form of epigenetic modification that regulates gene expression. However, there are limited data on the comprehensive analysis of DNA methylation regulated gene mutations (DMRGM) in acute myeloid leukemia (AML) mainly referring to DNA methyltransferase 3α (DNMT3A), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and Tet methylcytidine dioxygenase 2 (TET2).</p><p><strong>Results: </strong>A retrospective study of the clinical characteristics and gene mutations in 843 newly diagnosed non-M3 AML patients was conducted between January 2016 and August 2019. 29.7% (250/843) of patients presented with DMRGM. It was characterized by older age, higher white blood cell count, and higher platelet count (P < 0.05). DMRGM frequently coexisted with FLT3-ITD, NPM1, FLT3-TKD, and RUNX1 mutations (P < 0.05). The CR/CRi rate was only 60.3% in DMRGM patients, significantly lower than in non-DMRGM patients (71.0%, P = 0.014). In addition to being associated with poor overall survival (OS), DMRGM was also an independent risk factor for relapse-free survival (RFS) (HR: 1.467, 95% CI: 1.030-2.090, P = 0.034). Furthermore, OS worsened with an increasing burden of DMRGM. Patients with DMRGM may be benefit from hypomethylating drugs, and the unfavorable prognosis of DMRGM can be overcome by hematopoietic stem cell transplantation (HSCT). For external validation, the BeatAML database was downloaded, and a significant association between DMRGM and OS was confirmed (P < 0.05).</p><p><strong>Conclusion: </strong>Our study provides an overview of DMRGM in AML patients, which was identified as a risk factor for poor prognosis.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"54"},"PeriodicalIF":5.7,"publicationDate":"2023-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A Mongelli, S Panunzi, M Nesta, M Gottardi Zamperla, S Atlante, V Barbi, V Mongiardini, F Ferraro, S De Martino, L Cis, A Re, S Maltese, T Bachetti, M T La Rovere, F Martelli, M Pesce, S Nanni, M Massetti, A Pontecorvi, A Farsetti, C Gaetano
{"title":"Distinguishable DNA methylation defines a cardiac-specific epigenetic clock.","authors":"A Mongelli, S Panunzi, M Nesta, M Gottardi Zamperla, S Atlante, V Barbi, V Mongiardini, F Ferraro, S De Martino, L Cis, A Re, S Maltese, T Bachetti, M T La Rovere, F Martelli, M Pesce, S Nanni, M Massetti, A Pontecorvi, A Farsetti, C Gaetano","doi":"10.1186/s13148-023-01467-z","DOIUrl":"https://doi.org/10.1186/s13148-023-01467-z","url":null,"abstract":"<p><strong>Background: </strong>The present study investigates whether epigenetic differences emerge in the heart of patients undergoing cardiac surgery for an aortic valvular replacement (AVR) or coronary artery bypass graft (CABG). An algorithm is also established to determine how the pathophysiological condition might influence the human biological cardiac age.</p><p><strong>Results: </strong>Blood samples and cardiac auricles were collected from patients who underwent cardiac procedures: 94 AVR and 289 CABG. The CpGs from three independent blood-derived biological clocks were selected to design a new blood- and the first cardiac-specific clocks. Specifically, 31 CpGs from six age-related genes, ELOVL2, EDARADD, ITGA2B, ASPA, PDE4C, and FHL2, were used to construct the tissue-tailored clocks. The best-fitting variables were combined to define new cardiac- and blood-tailored clocks validated through neural network analysis and elastic regression. In addition, telomere length (TL) was measured by qPCR. These new methods revealed a similarity between chronological and biological age in the blood and heart; the average TL was significantly higher in the heart than in the blood. In addition, the cardiac clock discriminated well between AVR and CABG and was sensitive to cardiovascular risk factors such as obesity and smoking. Moreover, the cardiac-specific clock identified an AVR patient's subgroup whose accelerated bioage correlated with the altered ventricular parameters, including left ventricular diastolic and systolic volume.</p><p><strong>Conclusion: </strong>This study reports on applying a method to evaluate the cardiac biological age revealing epigenetic features that separate subgroups of AVR and CABG.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"53"},"PeriodicalIF":5.7,"publicationDate":"2023-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}