cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.30389136.v1
title: Identification of blood-derived DNA methylation biomarkers of glaucoma and intraocular pressure measurements in three European ancestry cohorts including the Canadian longitudinal study on aging

description: Glaucoma is a major cause of blindness globally and its prevalence rises with age. This study explored systemic blood-derived DNA methylation epigenetic biomarkers for association with glaucoma and intraocular pressure (IOP). Blood-derived DNA methylation (DNAm) was analyzed in 1,201 European participants from the Canadian Longitudinal Study on Aging (CLSA; Illumina EPIC v1 array) and 843 European participants from TwinsUK (450k array). An Epigenome-Wide Association Study (EWAS) for glaucoma and IOP was conducted, adjusting for age, sex, tobacco smoking, and leukocyte cell types. DNAm-based EpiScores estimates for 108 plasma protein levels were evaluated for associations with glaucoma and IOP. Additionally, ‘biological’ age acceleration, estimated using five established DNAm ‘clocks,’ was assessed for glaucoma and IOP and replicated in The Health and Retirement Study (HRS; <i>n</i> = 3,453). EWAS analyses of glaucoma and IOP in individual cohorts did not identify genome-wide significant associations. However, a combined EWAS for overlapping probes in both cohorts identified two epigenome-wide significant CpGs: cg03498697 in the <i>FRMD3</i> promoter (<i>p</i> = 6.86x10<sup>−8</sup>) and cg06044751 intronically within <i>PALLD</i> (<i>p</i> = 1.76x10<sup>−7</sup>). EpiScore analysis revealed one IOP Bonferroni-significant association with TNFRSF1B levels in the meta-analysis of both cohorts (<i>p</i> = 1.31x10<sup>−4</sup>). DNAm ‘clock’ analysis in the HRS identified a GrimAge-positive age acceleration associated with glaucoma (<i>p</i> = 0.01). This study identified significant epigenetic blood-derived biomarkers that are associated with glaucoma and IOP. These findings warrant replication in larger and more diverse populations as well as via longitudinal analysis to assess their robustness and potential predictive power.
DOI: 10.6084/m9.figshare.29285491
title: Differential methylation patterns in cord blood associated with prenatal exposure to neighborhood crime: an epigenome-wide association study and regional analysis

description: Exposure to prenatal social stressors during pregnancy is associated with adverse birth outcomes and has been linked to epigenetic changes in DNA methylation (DNAm); however, less understood is the effect of neighborhood-level stressors like crime during pregnancy on offspring DNAm. Using data from the Newborn Epigenetic Study, we conducted epigenome-wide and regional analyses of the association between exposure to neighborhood crime and DNAm in offspring cord blood using Illumina’s HumanMethylation450k BeadChip among 185 mother-offspring pairs. Prenatal exposure to neighborhood crime at the census block group level was mapped to participants' residential addresses during the gestational window from the date of last menstrual period to delivery. Models for the epigenome-wide and regional analyses were adjusted for maternal age, race/ethnicity, education, smoking, cell-type composition, and offspring sex. Genetic influence and gene expression enrichment were assessed using methylation quantitative trait loci (mQTLs) and expression quantitative trait methylation (eQTMs) analyses. Functional enrichment was determined using Gene Ontology and KEGG databases. We did not find evidence of epigenome-wide associations between prenatal neighborhood crime exposure and DNAm; however, we identified nine differentially methylated regions (DMRs) comprising 51 CpG sites associated with neighborhood crime. CpG sites within significant differentially methylated regions were associated with mQTLs at birth and eQTMs upon further examination. KEGG analysis identified a significant Th1 and Th2 cell differentiation pathway. Our results suggest potential links between prenatal neighborhood crime exposure and offspring DNAm; however, additional research is needed in larger cohorts across wider geographic areas to confirm our results.
DOI: 10.6084/m9.figshare.29285491.v1
title: Differential methylation patterns in cord blood associated with prenatal exposure to neighborhood crime: an epigenome-wide association study and regional analysis

description: Exposure to prenatal social stressors during pregnancy is associated with adverse birth outcomes and has been linked to epigenetic changes in DNA methylation (DNAm); however, less understood is the effect of neighborhood-level stressors like crime during pregnancy on offspring DNAm. Using data from the Newborn Epigenetic Study, we conducted epigenome-wide and regional analyses of the association between exposure to neighborhood crime and DNAm in offspring cord blood using Illumina’s HumanMethylation450k BeadChip among 185 mother-offspring pairs. Prenatal exposure to neighborhood crime at the census block group level was mapped to participants' residential addresses during the gestational window from the date of last menstrual period to delivery. Models for the epigenome-wide and regional analyses were adjusted for maternal age, race/ethnicity, education, smoking, cell-type composition, and offspring sex. Genetic influence and gene expression enrichment were assessed using methylation quantitative trait loci (mQTLs) and expression quantitative trait methylation (eQTMs) analyses. Functional enrichment was determined using Gene Ontology and KEGG databases. We did not find evidence of epigenome-wide associations between prenatal neighborhood crime exposure and DNAm; however, we identified nine differentially methylated regions (DMRs) comprising 51 CpG sites associated with neighborhood crime. CpG sites within significant differentially methylated regions were associated with mQTLs at birth and eQTMs upon further examination. KEGG analysis identified a significant Th1 and Th2 cell differentiation pathway. Our results suggest potential links between prenatal neighborhood crime exposure and offspring DNAm; however, additional research is needed in larger cohorts across wider geographic areas to confirm our results.
DOI: 10.6084/m9.figshare.30414510
title: Methylation differences between assisted reproductive technology-conceived and naturally conceived children near <i>BRCA1</i> and <i>NBR2</i>

description: Recent studies have shown that newborns conceived using assisted reproductive technology (ART) exhibited significantly different DNA methylation (DNAm) profiles at birth compared to those conceived naturally. Of note was the observation of increased DNAm at the promoter region of <i>BRCA1/NBR2</i> in ART-conceived newborns. However, it remains unclear if these DNAm differences persist after birth. Using the Norwegian Mother, Father, and Child Cohort Study (MoBa), a large-scale population-based pregnancy cohort with extensive longitudinal data collected through biological samples and questionnaires, we generated longitudinal DNAm data for 105 ART-conceived and 250 naturally conceived children at birth and at ages 3–22 years. DNAm differences in the <i>BRCA1</i>/<i>NBR2</i> promoter between ART- and naturally conceived children, at birth and postnatally, were tested using linear mixed model with adjustment for maternal and newborn covariates. While ART-conceived children showed subtle hypermethylation at birth and postnatally, the differences diminished over time and did not remain statistically significant after multiple testing correction. Our findings suggest that subtle hypermethylation at the <i>BRCA1/NBR2</i> promoter in ART-conceived children may represent an ART-associated epigenetic signature, although further studies in larger populations are needed to clarify its persistence and significance.
DOI: 10.6084/m9.figshare.30414510.v1
title: Methylation differences between assisted reproductive technology-conceived and naturally conceived children near <i>BRCA1</i> and <i>NBR2</i>

description: Recent studies have shown that newborns conceived using assisted reproductive technology (ART) exhibited significantly different DNA methylation (DNAm) profiles at birth compared to those conceived naturally. Of note was the observation of increased DNAm at the promoter region of <i>BRCA1/NBR2</i> in ART-conceived newborns. However, it remains unclear if these DNAm differences persist after birth. Using the Norwegian Mother, Father, and Child Cohort Study (MoBa), a large-scale population-based pregnancy cohort with extensive longitudinal data collected through biological samples and questionnaires, we generated longitudinal DNAm data for 105 ART-conceived and 250 naturally conceived children at birth and at ages 3–22 years. DNAm differences in the <i>BRCA1</i>/<i>NBR2</i> promoter between ART- and naturally conceived children, at birth and postnatally, were tested using linear mixed model with adjustment for maternal and newborn covariates. While ART-conceived children showed subtle hypermethylation at birth and postnatally, the differences diminished over time and did not remain statistically significant after multiple testing correction. Our findings suggest that subtle hypermethylation at the <i>BRCA1/NBR2</i> promoter in ART-conceived children may represent an ART-associated epigenetic signature, although further studies in larger populations are needed to clarify its persistence and significance.
DOI: 10.6084/m9.figshare.28297418
title: Deciphering the interplay between SETD2 mediated H3K36me3 and RNA N6-methyladenosine in clear cell renal cell carcinoma (ccRCC)

description: RNA N6-methyladenosine (m6A) plays diverse roles in RNA metabolism and its deregulation contributes to tumor initiation and progression. Clear cell renal cell carcinoma (ccRCC) is characterized by near ubiquitous loss of <i>VHL</i> followed by mutations in epigenetic regulators <i>PBRM1</i>, <i>SETD2</i>, and <i>BAP1</i>. Mutations in <i>SETD2</i>, a histone H3 lysine 36 trimethylase (H3K36me3), are associated with reduced survival, greater metastatic propensity, and metabolic reprogramming. While m6A and H3K36me3 deregulation are separately implicated in renal tumorigenesis, H3K36me3 may participate directly in m6A targeting, but the m6A-H3K36me3 interplay has not been investigated in the context of ccRCC. Using RCC-relevant SETD2 isogenic knockout and rescue cell line models, we demonstrate a dynamic redistribution of m6A in the SETD2 depleted transcriptome, with a subset of transcripts involved in metabolic reprogramming demonstrating SETD2 dependent m6A and expression level changes. Using a panel of six histone modifications we show that m6A redistributes to regions enriched in gained active enhancers upon <i>SETD2</i> inactivation. Finally, we demonstrate a reversal of transcriptomic programs involved in SETD2 loss mediated metabolic reprogramming, and reduced cell viability through pharmacologic inhibition or genetic ablation of m6A writer METTL3 specific to SETD2 deficient cells. Thus, targeting m6A may represent a novel therapeutic vulnerability in <i>SETD2</i> mutant ccRCC.
DOI: 10.6084/m9.figshare.28297418.v2
title: Deciphering the interplay between SETD2 mediated H3K36me3 and RNA N6-methyladenosine in clear cell renal cell carcinoma (ccRCC)

description: RNA N6-methyladenosine (m6A) plays diverse roles in RNA metabolism and its deregulation contributes to tumor initiation and progression. Clear cell renal cell carcinoma (ccRCC) is characterized by near ubiquitous loss of <i>VHL</i> followed by mutations in epigenetic regulators <i>PBRM1</i>, <i>SETD2</i>, and <i>BAP1</i>. Mutations in <i>SETD2</i>, a histone H3 lysine 36 trimethylase (H3K36me3), are associated with reduced survival, greater metastatic propensity, and metabolic reprogramming. While m6A and H3K36me3 deregulation are separately implicated in renal tumorigenesis, H3K36me3 may participate directly in m6A targeting, but the m6A-H3K36me3 interplay has not been investigated in the context of ccRCC. Using RCC-relevant SETD2 isogenic knockout and rescue cell line models, we demonstrate a dynamic redistribution of m6A in the SETD2 depleted transcriptome, with a subset of transcripts involved in metabolic reprogramming demonstrating SETD2 dependent m6A and expression level changes. Using a panel of six histone modifications we show that m6A redistributes to regions enriched in gained active enhancers upon <i>SETD2</i> inactivation. Finally, we demonstrate a reversal of transcriptomic programs involved in SETD2 loss mediated metabolic reprogramming, and reduced cell viability through pharmacologic inhibition or genetic ablation of m6A writer METTL3 specific to SETD2 deficient cells. Thus, targeting m6A may represent a novel therapeutic vulnerability in <i>SETD2</i> mutant ccRCC.
DOI: 10.6084/m9.figshare.28525360
title: SIRT1/DNMT3B-mediated epigenetic gene silencing in response to phytoestrogens in mammary epithelial cells

description: We performed an integrated analysis of genome-wide DNA methylation and expression datasets in normal cells and healthy animals exposed to polyphenols with estrogenic activity (i.e. phytoestrogens). We identified that phytoestrogens target genes linked to disrupted cellular homeostasis, e.g. genes limiting DNA break repair (<i>RNF169</i>) or promoting ribosomal biogenesis (<i>rDNA</i>). Existing evidence suggests that DNA methylation may be governed by sirtuin 1 (SIRT1) deacetylase via interactions with DNA methylating enzymes, specifically DNMT3B. Since SIRT1 was reported to be regulated by phytoestrogens, we test whether phytoestrogens suppress genes related to disrupted homeostasis via SIRT1/DNMT3B-mediated transcriptional silencing. Human MCF10A mammary epithelial cells were treated with phytoestrogens, pterostilbene (PTS) or genistein (GEN), followed by analysis of cell growth, DNA methylation, gene expression, and SIRT1/DNMT3B binding. SIRT1 occupancy at the selected phytoestrogen-target genes, <i>RNF169</i> and <i>rDNA</i>, was accompanied by consistent promoter hypermethylation and gene downregulation in response to GEN, but not PTS. GEN-mediated hypermethylation and SIRT1 binding were linked to a robust DNMT3B enrichment at <i>RNF169</i> and <i>rDNA</i> promoters. This was not observed in cells exposed to PTS, suggesting a distinct mechanism of action. Although both SIRT1 and DNMT3B bind to <i>RNF169</i> and <i>rDNA</i> promoters upon GEN, the two proteins do not co-occupy the regions. Depletion of SIRT1 abolishes GEN-mediated decrease in <i>rDNA</i> expression, suggesting SIRT1-dependent epigenetic suppression of <i>rDNA</i> by GEN. These findings enhance our understanding of the role of SIRT1-DNMT3B interplay in epigenetic mechanisms mediating the impact of phytoestrogens on cell biology and cellular homeostasis.
DOI: 10.6084/m9.figshare.28525360.v1
title: SIRT1/DNMT3B-mediated epigenetic gene silencing in response to phytoestrogens in mammary epithelial cells

description: We performed an integrated analysis of genome-wide DNA methylation and expression datasets in normal cells and healthy animals exposed to polyphenols with estrogenic activity (i.e. phytoestrogens). We identified that phytoestrogens target genes linked to disrupted cellular homeostasis, e.g. genes limiting DNA break repair (<i>RNF169</i>) or promoting ribosomal biogenesis (<i>rDNA</i>). Existing evidence suggests that DNA methylation may be governed by sirtuin 1 (SIRT1) deacetylase via interactions with DNA methylating enzymes, specifically DNMT3B. Since SIRT1 was reported to be regulated by phytoestrogens, we test whether phytoestrogens suppress genes related to disrupted homeostasis via SIRT1/DNMT3B-mediated transcriptional silencing. Human MCF10A mammary epithelial cells were treated with phytoestrogens, pterostilbene (PTS) or genistein (GEN), followed by analysis of cell growth, DNA methylation, gene expression, and SIRT1/DNMT3B binding. SIRT1 occupancy at the selected phytoestrogen-target genes, <i>RNF169</i> and <i>rDNA</i>, was accompanied by consistent promoter hypermethylation and gene downregulation in response to GEN, but not PTS. GEN-mediated hypermethylation and SIRT1 binding were linked to a robust DNMT3B enrichment at <i>RNF169</i> and <i>rDNA</i> promoters. This was not observed in cells exposed to PTS, suggesting a distinct mechanism of action. Although both SIRT1 and DNMT3B bind to <i>RNF169</i> and <i>rDNA</i> promoters upon GEN, the two proteins do not co-occupy the regions. Depletion of SIRT1 abolishes GEN-mediated decrease in <i>rDNA</i> expression, suggesting SIRT1-dependent epigenetic suppression of <i>rDNA</i> by GEN. These findings enhance our understanding of the role of SIRT1-DNMT3B interplay in epigenetic mechanisms mediating the impact of phytoestrogens on cell biology and cellular homeostasis.
DOI: 10.6084/m9.figshare.30300019
title: Decitabine-induced DNA methylation remodeling reveals targetable biological processes in gilthead seabream pituitary and liver explants

description: Epigenetic manipulations have the potential to improve traits in farmed fish. To explore this opportunity in the gilthead seabream (<i>Sparus aurata</i>), the catalytic domains of five DNA methyltransferases (DNMTs) were predicted by homology modeling, and their interaction with the inhibitor 5-aza-2′-deoxycytidine (DAC) was assessed by docking, revealing that the inhibitor can bind all DNMTs with similar energy. Then, pituitary and liver explants from gilthead seabream were exposed to DAC for 24 h, and changes in genome-wide DNA methylation (RRBS) and gene expression (RNA-seq) were assessed. In the liver, functional enrichment revealed upregulation of ribosome biogenesis and protein synthesis, while mitochondrial functioning, genome stability, and DNA and amino acid metabolism were downregulated. Exposed pituitaries displayed upregulation of ribosomal biogenesis and protein synthesis, alongside mitochondrial functioning and genome stability. Nucleotide-level methylomes were obtained for the first time in this species, with hypomethylated sites observed in 3’UTRs, promoter regions, and introns of highly expressed genes across both tissues. A higher level of DNA methylation at exons was found in highly expressed genes in the liver. The seabream pituitary was more permissive to DNA methylation remodeling than the liver. Functional Epigenetic Module analysis revealed seven interactome hotspots in liver and four in pituitary, mostly related to protein trafficking and signal transduction in the liver, and mitochondrial functioning in the pituitary, indicating that these functions can potentially be targeted by epigenetic interventions in seabream. The data resources generated in our study may be used to explore novel avenues to boost seabream performance and welfare.
DOI: 10.6084/m9.figshare.30300019.v1
title: Decitabine-induced DNA methylation remodeling reveals targetable biological processes in gilthead seabream pituitary and liver explants

description: Epigenetic manipulations have the potential to improve traits in farmed fish. To explore this opportunity in the gilthead seabream (<i>Sparus aurata</i>), the catalytic domains of five DNA methyltransferases (DNMTs) were predicted by homology modeling, and their interaction with the inhibitor 5-aza-2′-deoxycytidine (DAC) was assessed by docking, revealing that the inhibitor can bind all DNMTs with similar energy. Then, pituitary and liver explants from gilthead seabream were exposed to DAC for 24 h, and changes in genome-wide DNA methylation (RRBS) and gene expression (RNA-seq) were assessed. In the liver, functional enrichment revealed upregulation of ribosome biogenesis and protein synthesis, while mitochondrial functioning, genome stability, and DNA and amino acid metabolism were downregulated. Exposed pituitaries displayed upregulation of ribosomal biogenesis and protein synthesis, alongside mitochondrial functioning and genome stability. Nucleotide-level methylomes were obtained for the first time in this species, with hypomethylated sites observed in 3’UTRs, promoter regions, and introns of highly expressed genes across both tissues. A higher level of DNA methylation at exons was found in highly expressed genes in the liver. The seabream pituitary was more permissive to DNA methylation remodeling than the liver. Functional Epigenetic Module analysis revealed seven interactome hotspots in liver and four in pituitary, mostly related to protein trafficking and signal transduction in the liver, and mitochondrial functioning in the pituitary, indicating that these functions can potentially be targeted by epigenetic interventions in seabream. The data resources generated in our study may be used to explore novel avenues to boost seabream performance and welfare.
DOI: 10.6084/m9.figshare.29250815
title: Transcriptional signature of cardiac myocyte recovery in mice and human reveals persistent upregulation of epigenetic factors

description: Fibrosis, cardiac remodelling, and inflammation are hallmarks of heart failure. To date, there is no available pharmacological cure for heart failure, but mechanical unloading by implantation of a left ventricular assist device (LVAD) can lead to improved cardiac function in a subset of patients. This study aimed to identify the transcriptional response of left ventricular (LV) cardiac myocytes to mechanical unloading in a mouse model of reversible LV pressure overload and in failing human hearts after LVAD implantation. We found that partial recovery of ventricular dysfunction, LV hypertrophy, and gene expression programmes occurred in mice under reversible transverse aortic constriction (rTAC). Gene expression analysis in cardiac myocytes identified a lasting repression of mitochondrial gene expression resulting in compromised fatty acid oxidation in the mouse model of reversible pressure overload and in human LV samples after LVAD therapy and a persistent upregulation of epigenetic and transcriptional regulators. These findings underpin that recovery from heart failure involves complex gene regulatory networks and that mitochondrial dysfunction remains a challenge even after mechanical unloading. Further studies are needed to investigate the functional role of these factors in reverse remodelling and recovery of failing hearts.
DOI: 10.6084/m9.figshare.29250815.v1
title: Transcriptional signature of cardiac myocyte recovery in mice and human reveals persistent upregulation of epigenetic factors

description: Fibrosis, cardiac remodelling, and inflammation are hallmarks of heart failure. To date, there is no available pharmacological cure for heart failure, but mechanical unloading by implantation of a left ventricular assist device (LVAD) can lead to improved cardiac function in a subset of patients. This study aimed to identify the transcriptional response of left ventricular (LV) cardiac myocytes to mechanical unloading in a mouse model of reversible LV pressure overload and in failing human hearts after LVAD implantation. We found that partial recovery of ventricular dysfunction, LV hypertrophy, and gene expression programmes occurred in mice under reversible transverse aortic constriction (rTAC). Gene expression analysis in cardiac myocytes identified a lasting repression of mitochondrial gene expression resulting in compromised fatty acid oxidation in the mouse model of reversible pressure overload and in human LV samples after LVAD therapy and a persistent upregulation of epigenetic and transcriptional regulators. These findings underpin that recovery from heart failure involves complex gene regulatory networks and that mitochondrial dysfunction remains a challenge even after mechanical unloading. Further studies are needed to investigate the functional role of these factors in reverse remodelling and recovery of failing hearts.