Pub Date : 2023-04-12DOI: 10.1186/s13148-023-01480-2
Anne K Bozack, Sheryl L Rifas-Shiman, Diane R Gold, Zachary M Laubach, Wei Perng, Marie-France Hivert, Andres Cardenas
Background: 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.
Results: 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.
Conclusions: 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.
背景:表观遗传年龄加速(EAA)和表观遗传胎龄加速(EGAA)是生理发育的生物标志物,可能受到围产期环境的影响。本研究的目的是评估表观遗传时钟的表现,并确定EGAA和EAA在出生和童年时期的生物学和社会人口学相关性。在Viva项目出生前队列中,在脐带血(白细胞和有核红细胞,N = 485)和早期(N = 120,中位年龄= 3.2岁)和童年中期(N = 460,中位年龄= 7.7岁)的有核细胞中测量DNA甲基化。我们计算了表观遗传胎龄(EGA;Bohlin和Knight时钟)和表观遗传年龄(EA;Horvath和皮肤和血液时钟),以及EGAA和EAA的各自测量。我们使用相关性和中位数绝对误差来评估时钟相对于实足年龄的性能。我们使用相互调整的线性模型控制估计的细胞类型比例,测试了母子特征与EGAA和EAA的关联。我们还测试了出生时Horvath EA与儿童期EAA的关系。结果:Bohlin EGA与实足胎龄密切相关(Bohlin EGA r = 0.82, p)。结论:孕期吸烟和儿童性行为与EGAA和EAA在多个时间点存在相关性。进一步的研究可能会为围产期因素、儿童表观遗传衰老与整个生命周期的健康和发育之间的关系提供深入的见解。
{"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":null,"pages":null},"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}
Pub Date : 2023-04-08DOI: 10.1186/s13148-023-01476-y
Yang Pan, Xiao Sun, Zhijie Huang, Ruiyuan Zhang, Changwei Li, Amanda H Anderson, James P Lash, Tanika N Kelly
Background: 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.
Results: 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.
Conclusion: This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.
{"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":null,"pages":null},"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}
Pub Date : 2023-04-07DOI: 10.1186/s13148-023-01469-x
Joana B Serrano, Nils C Tabeling, Cindy M de Winter-Korver, Saskia K M van Daalen, Ans M M van Pelt, Callista L Mulder
Background: 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.
Results: 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.
Conclusions: 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.
{"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":null,"pages":null},"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}
Pub Date : 2023-04-07DOI: 10.1186/s13148-023-01475-z
Yili Ping, Jingjuan Huang, Jichao Zhu, Zujun Sun, Anquan Shang, Chen Chen, Wenfang Liu, Dong Li
Background: Lung adenocarcinoma (LUAD) has a high incidence and recurrence rate. N6-methyladenosine (m6A) modification of RNA has become a promising epigenetic marker in tumors. The dysregulation of both RNA m6A levels and m6A 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 m6A, but the relevant profile in LUAD remains unclear.
Results: The m6A levels of total RNA were decreased in LUAD tumor tissues and cells. Multiple m6A regulators were abnormally expressed at both the RNA and protein levels, and were related in expression patterns and functionally synergistic. Our microarray revealed 2846 m6A-modified lncRNA transcripts as well as its molecular features, 143 of which were differentially m6A-modified and manifested a negative correlation between expression levels and m6A modification levels. More than half of the differentially m6A-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 m6A-induced pathogenicity in LUAD.
Conclusions: These data have demonstrated that differential RNA m6A modification and m6A 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 m6A-modified lncRNAs in LUAD.
{"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":null,"pages":null},"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}
Pub Date : 2023-04-07DOI: 10.1186/s13148-023-01473-1
Guoying Wang, Richard Xu, Boyang Zhang, Xiumei Hong, Tami R Bartell, Colleen Pearson, Liming Liang, Xiaobin Wang
Background: 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.
Methods: 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.
Results: 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%.
Conclusions: 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.
背景:子宫内暴露于糖尿病已被证明有助于早产,尽管潜在的生物学机制尚未完全阐明。在子宫内建立的胎儿表观遗传变异可能是一个可能的途径。本研究旨在调查子宫内暴露于糖尿病是否与新生儿DNA甲基化变化有关,以及在种族多样化的出生队列人群中,已确定的CpG位点是否介导糖尿病和早产之间的关联。方法:本研究纳入954对母婴。使用Illumina Infinium MethylationEPIC BeadChip 850 K阵列平台测定脐带血中的甲基化水平。子宫内暴露于糖尿病是由母体妊娠期或妊娠期糖尿病的存在来定义的。早产被定义为出生时胎龄少于37周。采用线性回归分析鉴定差异甲基化的CpG位点。使用DMRcate Package鉴定差异甲基化区域。结果:126例(13%)新生儿为妊娠期糖尿病母亲所生,173例(18%)新生儿为早产,41例新生儿为早产和妊娠期糖尿病母亲所生。全基因组CpG分析发现,在FDR阈值为5%时,脐带血中18个CpG位点被母体糖尿病状态差异甲基化。这些重要的CpG位点被定位到12个已知基因,其中一个被注释为基因Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB)。一致地,两个确定的显著甲基化区域之一与HLA-DMB重叠。鉴定出的差异甲基化的CpG位点介导了妊娠期糖尿病和早产之间61%的关联。结论:在这个美国出生队列中,我们发现母亲糖尿病与胎儿DNA甲基化模式改变有关,这在很大程度上解释了糖尿病和早产之间的联系。
{"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":null,"pages":null},"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}
Pub Date : 2023-04-01DOI: 10.1186/s13148-023-01472-2
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
Background: 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.
Results: 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.
Conclusions: 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.
背景:近年来,结直肠癌(CRC)的发病率有所上升。准确识别肿瘤标志物已成为结直肠癌研究的重点。早期和频繁的DNA甲基化往往发生在癌症中。因此,鉴定准确的甲基化生物标志物将提高结直肠癌治疗的疗效。神经红蛋白(NGB)与神经和肿瘤疾病有关。然而,目前还没有关于NGB参与CRC的表观遗传调控的报道。结果:NGB在大多数结直肠癌组织和细胞系中表达下调或沉默。在肿瘤组织中检测到NGB的高甲基化,而在正常组织中没有甲基化或甲基化频率很低。过表达NGB诱导G2/M期阻滞和凋亡,抑制体外增殖、迁移、侵袭,抑制体内CRC肿瘤生长和血管生成。基于Isobaric tag for relative and absolute quantitation (Itraq)的蛋白质组学鉴定出肿瘤微环境中约40%与细胞粘附、侵袭和肿瘤血管形成相关的蛋白质,其中GPR35被证明对ngb调控的CRC肿瘤血管生成抑制至关重要。结论:NGB是一种表观遗传沉默因子,通过GPR35抑制结直肠癌的转移。有望成为一种潜在的癌症风险评估因子,成为CRC早期诊断和预后评估的有价值的生物标志物。
{"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":null,"pages":null},"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}
Pub Date : 2023-03-30DOI: 10.1186/s13148-023-01465-1
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
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
{"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":null,"pages":null},"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}
Pub Date : 2023-03-30DOI: 10.1186/s13148-023-01468-y
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
Background: 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.
Results: 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 × 10-11) and biological processes "skeletal system development" (q = 1.89 × 10-23). 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 × 10-6) and atherosclerosis (p = 4.9 × 10-4).
Conclusion: 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.
{"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":null,"pages":null},"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}
Background: 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).
Results: 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).
Conclusion: Our study provides an overview of DMRGM in AML patients, which was identified as a risk factor for poor prognosis.
背景:DNA甲基化是一种调控基因表达的表观遗传修饰。然而,关于急性髓性白血病(AML)中DNA甲基化调控基因突变(DMRGM)的综合分析数据有限,主要涉及DNA甲基转移酶3α(DNMT3A)、异柠檬酸脱氢酶1(IDH1)、异柠檬酸脱氢酶2(IDH2)和Tet甲胞苷二氧酶2(TET2):2016年1月至2019年8月期间,对843名新确诊的非M3 AML患者的临床特征和基因突变情况进行了回顾性研究。29.7%的患者(250/843)表现为DMRGM。其特点是年龄较大、白细胞计数较高和血小板计数较高:我们的研究提供了 AML 患者中 DMRGM 的概况,它被确定为预后不良的风险因素。
{"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":null,"pages":null},"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}
Pub Date : 2023-03-29DOI: 10.1186/s13148-023-01467-z
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
Background: 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.
Results: 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.
Conclusion: This study reports on applying a method to evaluate the cardiac biological age revealing epigenetic features that separate subgroups of AVR and CABG.
{"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":null,"pages":null},"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}