cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.28491151
title: A polyepigenetic glucocorticoid exposure score and HPA axis-related DNA methylation are associated with gestational epigenetic aging

description: Gestational epigenetic aging (GEA) is a novel approach for characterizing associations between prenatal exposures and postnatal risks. Psychosocial adversity in pregnancy may influence GEA, but the molecular mechanisms are not well understood. DNA methylation to glucocorticoid regulation and hypothalamic-pituitary-adrenal (HPA) axis genes are implicated but have not been fully examined in association with GEA. This study investigated whether a polyepigenetic glucocorticoid exposure score (PGES) and HPA axis gene (<i>NR3C1, HSD11B2, FKBP5</i>) methylation were associated with GEA, and whether associations were sex-specific. Participants were from a prospective cohort of racial/ethnic diverse and socially disadvantaged pregnant women and infants (<i>n</i> = 200). DNA methylation variables were estimated using umbilical cord blood. PGES was derived with CpGs shown to be sensitive to synthetic dexamethasone exposure. <i>NR3C1</i>, <i>HSD11B2</i>, and <i>FKBP5</i> methylation was summarized via factor analysis. We found that PGES (β = -1.12, SE = 0.47, <i>p</i> = 0.02) and several <i>NR3C1</i> and <i>FKBP5</i> factor scores were associated with decelerated GEA (all <i>p</i> &lt; 0.05). A significant sex interaction was observed for <i>FKBP5</i> factor score 3 (β = -0.34, SE = 0.15, <i>p</i> = 0.02) suggesting decelerated GEA for males but not females. This study showed that glucocorticoid regulation-related DNA methylation was associated with a decelerated aging phenotype at birth that might indicate a neonatal risk.
DOI: 10.6084/m9.figshare.28491151.v1
title: A polyepigenetic glucocorticoid exposure score and HPA axis-related DNA methylation are associated with gestational epigenetic aging

description: Gestational epigenetic aging (GEA) is a novel approach for characterizing associations between prenatal exposures and postnatal risks. Psychosocial adversity in pregnancy may influence GEA, but the molecular mechanisms are not well understood. DNA methylation to glucocorticoid regulation and hypothalamic-pituitary-adrenal (HPA) axis genes are implicated but have not been fully examined in association with GEA. This study investigated whether a polyepigenetic glucocorticoid exposure score (PGES) and HPA axis gene (<i>NR3C1, HSD11B2, FKBP5</i>) methylation were associated with GEA, and whether associations were sex-specific. Participants were from a prospective cohort of racial/ethnic diverse and socially disadvantaged pregnant women and infants (<i>n</i> = 200). DNA methylation variables were estimated using umbilical cord blood. PGES was derived with CpGs shown to be sensitive to synthetic dexamethasone exposure. <i>NR3C1</i>, <i>HSD11B2</i>, and <i>FKBP5</i> methylation was summarized via factor analysis. We found that PGES (β = -1.12, SE = 0.47, <i>p</i> = 0.02) and several <i>NR3C1</i> and <i>FKBP5</i> factor scores were associated with decelerated GEA (all <i>p</i> &lt; 0.05). A significant sex interaction was observed for <i>FKBP5</i> factor score 3 (β = -0.34, SE = 0.15, <i>p</i> = 0.02) suggesting decelerated GEA for males but not females. This study showed that glucocorticoid regulation-related DNA methylation was associated with a decelerated aging phenotype at birth that might indicate a neonatal risk.
DOI: 10.6084/m9.figshare.30127396
title: Tributyltin chloride alters the structural, genomic, and epigenomic integrity of postejaculatory mammalian sperm

description: A global priority for ameliorating male factor infertility includes identification of environmental factors and mechanisms that impact sperm function. Detection of endocrine disrupting chemicals (EDC) in seminal plasma and within the female reproductive tract has created an urgent need to understand how environmental stressors alter postejaculatory sperm function. Tributyltin chloride (TBT) is an EDC and epigenetic modifier that causes reproductive disorders. The consequences of TBT exposure on postejaculatory sperm remain unknown. The present study was aimed at identifying structural, genomic, and epigenomic consequences of TBT exposure to postejaculatory sperm. Bovine sperm were exposed to TBT (0, 1, 10, 100 nM) for 24 h followed by quantification of sperm kinematics, DNA integrity, and methylation status. No differences were detected in sperm kinematics or capacitation status. However, acrosome integrity was compromised at both 0 and 24 h (<i>P</i> ≤ 0.05). Sperm DNA integrity was also negatively affected after 24 h. Whole-genome methyl-seq revealed ~750 differentially methylated regions (DMRs) associated with exposure to TBT. Ingenuity Pathway Analyses and Gene Ontology identified embryo development, cell signaling, and transcriptional regulation as the most relevant bio-functions of TBT altered DMRs. In conclusion, postejaculatory mammalian sperm exposure to TBT negatively affected parameters important for sperm function while altering DNA integrity and the methylation profile of gene promoter regions. Consequences of sperm exposure to TBT included cellular and molecular mechanisms that are important for sperm function but remain undetected by routine clinical analyses. These findings provide new insight into environmental impacts on postejaculatory sperm structure and function.
DOI: 10.6084/m9.figshare.30127396.v1
title: Tributyltin chloride alters the structural, genomic, and epigenomic integrity of postejaculatory mammalian sperm

description: A global priority for ameliorating male factor infertility includes identification of environmental factors and mechanisms that impact sperm function. Detection of endocrine disrupting chemicals (EDC) in seminal plasma and within the female reproductive tract has created an urgent need to understand how environmental stressors alter postejaculatory sperm function. Tributyltin chloride (TBT) is an EDC and epigenetic modifier that causes reproductive disorders. The consequences of TBT exposure on postejaculatory sperm remain unknown. The present study was aimed at identifying structural, genomic, and epigenomic consequences of TBT exposure to postejaculatory sperm. Bovine sperm were exposed to TBT (0, 1, 10, 100 nM) for 24 h followed by quantification of sperm kinematics, DNA integrity, and methylation status. No differences were detected in sperm kinematics or capacitation status. However, acrosome integrity was compromised at both 0 and 24 h (<i>P</i> ≤ 0.05). Sperm DNA integrity was also negatively affected after 24 h. Whole-genome methyl-seq revealed ~750 differentially methylated regions (DMRs) associated with exposure to TBT. Ingenuity Pathway Analyses and Gene Ontology identified embryo development, cell signaling, and transcriptional regulation as the most relevant bio-functions of TBT altered DMRs. In conclusion, postejaculatory mammalian sperm exposure to TBT negatively affected parameters important for sperm function while altering DNA integrity and the methylation profile of gene promoter regions. Consequences of sperm exposure to TBT included cellular and molecular mechanisms that are important for sperm function but remain undetected by routine clinical analyses. These findings provide new insight into environmental impacts on postejaculatory sperm structure and function.
DOI: 10.6084/m9.figshare.29558678
title: CpG island demethylation and recruitment of SP1 to the promoter region regulates human thymic stromal lymphopoietin expression

description: Thymic Stromal Lymphopoietin (TSLP), an immunomodulatory cytokine, plays a pivotal role in the development and progression of atopic and allergic diseases. Atopy follows familial inheritance, and genome-wide studies have shown association of atopy with TSLP polymorphisms. Here, we analysed the conserved transcriptional regulatory elements in the human TSLP promoter, which revealed the presence of three CpG islands. Demethylation of the CpG island using 5-azacytidine or siRNA-mediated knockdown of DNA methyl transferases significantly upregulated TSLP expression. Sequence analysis revealed the presence of two overlapping SP1 transcription factor DNA-binding sites (DBSs), between −1494 and −1510 nucleotides on the human TSLP promoter. Further experiments showed that demethylation of the CpG island enables the binding of SP1 to its cognate DBS present on the TSLP promoter, resulting in its transcriptional activation. Moreover, retinoic acid-induced transcription of human TSLP was associated with CpG island demethylation and SP1 binding to the TSLP promoter. These findings unravel a distinct mechanism of transcriptional regulation of the human TSLP gene and suggest possible epigenetic regulation of TSLP expression in modulating atopic and allergic disease severity in different individuals.
DOI: 10.6084/m9.figshare.29824889
title: Association of systemic immune-inflammation index (SII) with epigenetic age acceleration in adults: insights from NHANES

description: The Systemic Immune-Inflammation Index (SII), a marker of systemic inflammation, has been linked to various age-related diseases, but its association with Epigenetic Age Acceleration (EAA) remains underexplored. This study aimed to investigate the SII and EAA relationship. We analysed data from 1,915 participants from the National Health and Nutrition Examination Survey (NHANES). SII was calculated as platelet count × (neutrophil count/lymphocyte count). EAA was defined as HorvathAccel, HannumAccel, Skin&BloodAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. These metrics were derived utilizing the residual method. Multivariate linear regression, smooth curve fitting, threshold effect analyses, and subgroup analyses were employed to assess the relationship between the SII and EAA. Higher SII levels were significantly associated with HannumAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. Threshold effect analyses revealed non-linear relationships, with inflection points at SII values of 24.200, 12.553, 7.766, and 10.133, respectively. Subgroup analyses identified sex, age, poverty-to-income ratio, and marital status as significant effect modifiers. The elevated SII was associated with accelerated epigenetic ageing.
DOI: 10.6084/m9.figshare.29824889.v1
title: Association of systemic immune-inflammation index (SII) with epigenetic age acceleration in adults: insights from NHANES

description: The Systemic Immune-Inflammation Index (SII), a marker of systemic inflammation, has been linked to various age-related diseases, but its association with Epigenetic Age Acceleration (EAA) remains underexplored. This study aimed to investigate the SII and EAA relationship. We analysed data from 1,915 participants from the National Health and Nutrition Examination Survey (NHANES). SII was calculated as platelet count × (neutrophil count/lymphocyte count). EAA was defined as HorvathAccel, HannumAccel, Skin&BloodAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. These metrics were derived utilizing the residual method. Multivariate linear regression, smooth curve fitting, threshold effect analyses, and subgroup analyses were employed to assess the relationship between the SII and EAA. Higher SII levels were significantly associated with HannumAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. Threshold effect analyses revealed non-linear relationships, with inflection points at SII values of 24.200, 12.553, 7.766, and 10.133, respectively. Subgroup analyses identified sex, age, poverty-to-income ratio, and marital status as significant effect modifiers. The elevated SII was associated with accelerated epigenetic ageing.
DOI: 10.6084/m9.figshare.28539179.v1
title: Single and multi-omic characterization of a porcine model of ethanol-induced hepatic fibrosis

description: Cirrhosis is a form of end-stage liver disease characterized by extensive hepatic fibrosis and loss of liver parenchyma. It is most commonly the result of long-term alcohol abuse in the United States. Large animal models of cirrhosis, as well as of one of its common long-term sequelae, HCC, are needed to study novel and emerging therapeutic interventions. In the present study, liver fibrosis was induced in the Oncopig cancer model, a large animal HCC model, via intrahepatic, intra-arterial ethanol infusion. Liver sections from five fibrosis induced and five age-matched controls were harvested for RNA-seq (mRNA and lncRNA), small RNA-seq (miRNA), and reduced representation bisulfite sequencing (RRBS; DNA methylation). Single- and multi-omic analysis was performed to investigate the transcriptomic and epigenomic mechanisms associated with fibrosis deposition in this model. A total of 3,439 genes, 70 miRNAs, 452 lncRNAs, and 7,715 methylation regions were found to be differentially regulated through individual single-omic analysis. Pathway analysis indicated differentially expressed genes were associated with collagen synthesis and turnover, hepatic metabolic functions such as ethanol and lipid metabolism, and proliferative and anti-proliferative pathways including PI3K and BAX/BCL signaling pathways. Multi-omic latent variable analysis demonstrated significant concordance with the single-omic analysis. lncRNA’s associated with <i>UHRF1BP1L</i> and <i>S1PR1</i> genes were found to reliably discriminate the two arms of the study. These genes were previously implicated in human cancer development and vasculogenesis, respectively. These findings support the validity and translatability of this model as a useful preclinical tool in the study of alcoholic liver disease and its treatment.
DOI: 10.6084/m9.figshare.29558678.v1
title: CpG island demethylation and recruitment of SP1 to the promoter region regulates human thymic stromal lymphopoietin expression

description: Thymic Stromal Lymphopoietin (TSLP), an immunomodulatory cytokine, plays a pivotal role in the development and progression of atopic and allergic diseases. Atopy follows familial inheritance, and genome-wide studies have shown association of atopy with TSLP polymorphisms. Here, we analysed the conserved transcriptional regulatory elements in the human TSLP promoter, which revealed the presence of three CpG islands. Demethylation of the CpG island using 5-azacytidine or siRNA-mediated knockdown of DNA methyl transferases significantly upregulated TSLP expression. Sequence analysis revealed the presence of two overlapping SP1 transcription factor DNA-binding sites (DBSs), between −1494 and −1510 nucleotides on the human TSLP promoter. Further experiments showed that demethylation of the CpG island enables the binding of SP1 to its cognate DBS present on the TSLP promoter, resulting in its transcriptional activation. Moreover, retinoic acid-induced transcription of human TSLP was associated with CpG island demethylation and SP1 binding to the TSLP promoter. These findings unravel a distinct mechanism of transcriptional regulation of the human TSLP gene and suggest possible epigenetic regulation of TSLP expression in modulating atopic and allergic disease severity in different individuals.
DOI: 10.6084/m9.figshare.28539179
title: Single and multi-omic characterization of a porcine model of ethanol-induced hepatic fibrosis

description: Cirrhosis is a form of end-stage liver disease characterized by extensive hepatic fibrosis and loss of liver parenchyma. It is most commonly the result of long-term alcohol abuse in the United States. Large animal models of cirrhosis, as well as of one of its common long-term sequelae, HCC, are needed to study novel and emerging therapeutic interventions. In the present study, liver fibrosis was induced in the Oncopig cancer model, a large animal HCC model, via intrahepatic, intra-arterial ethanol infusion. Liver sections from five fibrosis induced and five age-matched controls were harvested for RNA-seq (mRNA and lncRNA), small RNA-seq (miRNA), and reduced representation bisulfite sequencing (RRBS; DNA methylation). Single- and multi-omic analysis was performed to investigate the transcriptomic and epigenomic mechanisms associated with fibrosis deposition in this model. A total of 3,439 genes, 70 miRNAs, 452 lncRNAs, and 7,715 methylation regions were found to be differentially regulated through individual single-omic analysis. Pathway analysis indicated differentially expressed genes were associated with collagen synthesis and turnover, hepatic metabolic functions such as ethanol and lipid metabolism, and proliferative and anti-proliferative pathways including PI3K and BAX/BCL signaling pathways. Multi-omic latent variable analysis demonstrated significant concordance with the single-omic analysis. lncRNA’s associated with <i>UHRF1BP1L</i> and <i>S1PR1</i> genes were found to reliably discriminate the two arms of the study. These genes were previously implicated in human cancer development and vasculogenesis, respectively. These findings support the validity and translatability of this model as a useful preclinical tool in the study of alcoholic liver disease and its treatment.
DOI: 10.6084/m9.figshare.29086534
title: Blood transcriptomic associations of epigenetic age in adolescents

description: Epigenetic aging in early life remains poorly characterized, and patterns of gene expression can provide biologically meaningful insights. Blood DNA methylation was measured using the Illumina EPICv1.0 array and RNA sequencing was performed in blood in 174 adolescent participants (age range: 14–15 years) from the CHAMACOS cohort. Thirteen widely used epigenetic clocks were calculated, and their associations with transcriptome-wide RNA expression were tested using the <i>limma-voom</i> pipeline. We found evidence for substantial shared associations with RNA expression between different epigenetic clocks, including differential expression of <i>MYO6</i> and <i>ZBTB38</i> across five clocks. The epiTOC2, principal component (PC) PhenoAge, Hannum, PedBE and PC Hannum clocks were associated with differential expression of the highest number of RNAs, exhibiting associations with 22, 8, 5, 3, and 2 transcripts respectively. Generally, biological clocks were associated with differential expression of more genes than chronological clocks, and PC clocks were associated with differential expression of more genes relative to their CpG-trained counterparts. A total of 17 associations in our study were replicated in an independent adult sample (age range: 40–54 years). Our findings support the biological relevance of epigenetic clocks in adolescents and provide direction for selection of epigenetic ageing biomarkers in adolescent research.
DOI: 10.6084/m9.figshare.29086534.v1
title: Blood transcriptomic associations of epigenetic age in adolescents

description: Epigenetic aging in early life remains poorly characterized, and patterns of gene expression can provide biologically meaningful insights. Blood DNA methylation was measured using the Illumina EPICv1.0 array and RNA sequencing was performed in blood in 174 adolescent participants (age range: 14–15 years) from the CHAMACOS cohort. Thirteen widely used epigenetic clocks were calculated, and their associations with transcriptome-wide RNA expression were tested using the <i>limma-voom</i> pipeline. We found evidence for substantial shared associations with RNA expression between different epigenetic clocks, including differential expression of <i>MYO6</i> and <i>ZBTB38</i> across five clocks. The epiTOC2, principal component (PC) PhenoAge, Hannum, PedBE and PC Hannum clocks were associated with differential expression of the highest number of RNAs, exhibiting associations with 22, 8, 5, 3, and 2 transcripts respectively. Generally, biological clocks were associated with differential expression of more genes than chronological clocks, and PC clocks were associated with differential expression of more genes relative to their CpG-trained counterparts. A total of 17 associations in our study were replicated in an independent adult sample (age range: 40–54 years). Our findings support the biological relevance of epigenetic clocks in adolescents and provide direction for selection of epigenetic ageing biomarkers in adolescent research.
DOI: 10.6084/m9.figshare.29126989
title: PRMT1 promotes immune escape in hepatocellular carcinoma by regulating arginine methylation modification of MYC protein

description: Arginine methyltransferase 1 (PRMT1) is widely recognized as an oncogene in various cancers. However, its specific role and underlying mechanisms in hepatocellular carcinoma (HCC) remain insufficiently understood. This study investigated the function of PRMT1 in HCC development and immune evasion. A comprehensive approach combining database analysis (including TCGA, The Human Protein Atlas, Kaplan-Meier Plotter, and TIMER2.0), molecular techniques (such as RT-qPCR, Western blot analysis, and co-immunoprecipitation), cell-based assays (including MTT, colony formation, transwell, and T cell killing assays), and <i>in vivo</i> models was employed to explore PRMT1’s role in HCC. The findings revealed a marked upregulation of PRMT1 in both HCC clinical samples and cell lines. Depletion of PRMT1 inhibited cell proliferation and immune evasion while reducing cell migration and invasion. Mechanistically, PRMT1 was shown to interact with MYC, facilitating its arginine methylation and enhancing its protein stability. Moreover, re-expression of MYC significantly reversed the anti-tumour effects associated with PRMT1 depletion. <i>In vivo</i> experiments further corroborated these results. Collectively, PRMT1 promotes HCC progression and immune escape by mediating ADMA methylation of MYC, thereby regulating its stability and expression.
DOI: 10.6084/m9.figshare.29126989.v1
title: PRMT1 promotes immune escape in hepatocellular carcinoma by regulating arginine methylation modification of MYC protein

description: Arginine methyltransferase 1 (PRMT1) is widely recognized as an oncogene in various cancers. However, its specific role and underlying mechanisms in hepatocellular carcinoma (HCC) remain insufficiently understood. This study investigated the function of PRMT1 in HCC development and immune evasion. A comprehensive approach combining database analysis (including TCGA, The Human Protein Atlas, Kaplan-Meier Plotter, and TIMER2.0), molecular techniques (such as RT-qPCR, Western blot analysis, and co-immunoprecipitation), cell-based assays (including MTT, colony formation, transwell, and T cell killing assays), and <i>in vivo</i> models was employed to explore PRMT1’s role in HCC. The findings revealed a marked upregulation of PRMT1 in both HCC clinical samples and cell lines. Depletion of PRMT1 inhibited cell proliferation and immune evasion while reducing cell migration and invasion. Mechanistically, PRMT1 was shown to interact with MYC, facilitating its arginine methylation and enhancing its protein stability. Moreover, re-expression of MYC significantly reversed the anti-tumour effects associated with PRMT1 depletion. <i>In vivo</i> experiments further corroborated these results. Collectively, PRMT1 promotes HCC progression and immune escape by mediating ADMA methylation of MYC, thereby regulating its stability and expression.