cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.12054021.v1
title: Comparative analysis of genome-wide DNA methylation in <i>Neurospora</i>

description: DNA methylation is an epigenetic mark that plays an important role in genetic regulation in eukaryotes. Major progress has been made in dissecting the molecular pathways that regulate DNA methylation. Yet, little is known about DNA methylation variation over evolutionary time. Here we present an investigation of the variation of DNA methylation and transposable element (TE) content in species of the filamentous ascomycetes <i>Neurospora</i>. We generated genome-wide DNA methylation data at single-base resolution, together with genomic TE content and gene expression data, of 10 individuals representing five closely related <i>Neurospora</i> species. We found that the methylation levels were low (ranging from 1.3% to 2.5%) and varied among the genomes in a species-specific way. Furthermore, we found that the TEs over 400 bp long were targeted by DNA methylation, and in all genomes, high methylation correlated with low GC, confirming a conserved link between DNA methylation and Repeat Induced Point (RIP) mutations in this group of fungi. Both TE content and DNA methylation pattern showed phylogenetic signal, and the species with the highest TE load (<i>N. crassa</i>) also exhibited the highest methylation level per TE. Our results suggest that DNA methylation is an evolvable trait and indicate that the genomes of <i>Neurospora</i> are shaped by an evolutionary arms race between TEs and host defence.
DOI: 10.6084/m9.figshare.12851672
title: Cytosine methylation patterns suggest a role of methylation in plastic and adaptive responses to temperature in European grayling (<i>Thymallus thymallus</i>) populations

description: Temperature is a key environmental parameter affecting both the phenotypes and distributions of organisms, particularly ectotherms. Rapid organismal responses to thermal environmental changes have been described for several ectotherms; however, the underlying molecular mechanisms often remain unclear. Here, we studied whole genome cytosine methylation patterns of European grayling (<i>Thymallus thymallus</i>) embryos from five populations with contemporary adaptations of early life history traits at either ‘colder’ or ‘warmer’ spawning grounds. We reared fish embryos in a common garden experiment using two temperatures that resembled the ‘colder’ and ‘warmer’ conditions of the natal natural environments. Genome-wide methylation patterns were similar in populations originating from colder thermal origin subpopulations, whereas single nucleotide polymorphisms uncovered from the same data identified strong population structure among isolated populations, but limited structure among interconnected populations. This was surprising because the previously studied gene expression response among populations was mostly plastic, and mainly influenced by the developmental temperature. These findings support the hypothesis of the magnified role of epigenetic mechanisms in modulating plasticity. The abundance of consistently changing methylation loci between two warmer-to-colder thermal origin population pairs suggests that local adaptation has shaped the observed methylation patterns. The dynamic nature of the methylomes was further highlighted by genome-wide and site-specific plastic responses. Our findings support both the presence of a plastic response in a subset of CpG loci, and the evolutionary role of methylation divergence between populations adapting to contrasting thermal environments.
DOI: 10.6084/m9.figshare.12851672.v1
title: Cytosine methylation patterns suggest a role of methylation in plastic and adaptive responses to temperature in European grayling (<i>Thymallus thymallus</i>) populations

description: Temperature is a key environmental parameter affecting both the phenotypes and distributions of organisms, particularly ectotherms. Rapid organismal responses to thermal environmental changes have been described for several ectotherms; however, the underlying molecular mechanisms often remain unclear. Here, we studied whole genome cytosine methylation patterns of European grayling (<i>Thymallus thymallus</i>) embryos from five populations with contemporary adaptations of early life history traits at either ‘colder’ or ‘warmer’ spawning grounds. We reared fish embryos in a common garden experiment using two temperatures that resembled the ‘colder’ and ‘warmer’ conditions of the natal natural environments. Genome-wide methylation patterns were similar in populations originating from colder thermal origin subpopulations, whereas single nucleotide polymorphisms uncovered from the same data identified strong population structure among isolated populations, but limited structure among interconnected populations. This was surprising because the previously studied gene expression response among populations was mostly plastic, and mainly influenced by the developmental temperature. These findings support the hypothesis of the magnified role of epigenetic mechanisms in modulating plasticity. The abundance of consistently changing methylation loci between two warmer-to-colder thermal origin population pairs suggests that local adaptation has shaped the observed methylation patterns. The dynamic nature of the methylomes was further highlighted by genome-wide and site-specific plastic responses. Our findings support both the presence of a plastic response in a subset of CpG loci, and the evolutionary role of methylation divergence between populations adapting to contrasting thermal environments.
DOI: 10.6084/m9.figshare.12851663
title: Genome-wide DNA methylation differences and polychlorinated biphenyl (PCB) exposure in a US population

description: Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR &lt; 0.05). These CpGs were enriched in active promoter and transcription associated regions (p
DOI: 10.6084/m9.figshare.12851669
title: Expression of UDP Glucuronosyltransferases <i>2B15</i> and <i>2B17</i> is associated with methylation status in prostate cancer cells

description: Studies have suggested that abrogated expression of detoxification enzymes, UGT2B15 and UGT2B17, are associated with prostate tumour risk and progression. We investigated the role of EGF on the expression of these enzymes since it interacts with signalling pathways to also affect prostate tumour progression and is additionally associated with decreased DNA methylation. The expression of <i>UGT2B15, UGT2B17</i>, <i>de novo</i> methyltransferases, <i>DNMT3A</i> and <i>DNMT3B</i> was assessed in prostate cancer cells (LNCaP) treated with EGF, an EGFR inhibitor PD16893, and the methyltransferase inhibitor, 5-azacytidine, respectively. The results showed that EGF treatment decreased levels of expression of all four genes and that their expression was reversed by PD16893. Treatment with 5-azacytidine, markedly decreased expression of <i>UGT2B15</i> and <i>UGT2B17</i> over 85% as well as significantly decreased expression of <i>DNMT3B</i>, but not the expression of <i>DNMT3A. DNMT3B</i> siRNA treated LNCaP cells had decreased expression of <i>UGT2B15</i> and <i>UGT2B17</i>, while <i>DNMT3A</i> siRNA treated cells had only moderately decreased <i>UGT2B15</i> expression. Treatment with DNMT methyltransferase inhibitor, RG108, significantly decreased <i>UGT2B17</i> expression. Additionally, methylation differences between prostate cancer samples and benign prostate samples from an Illumina 450K Methylation Array study were assessed. The results taken together suggest that hypomethylation of the <i>UGT2B15</i> and <i>UGT2B17</i> genes contributes to increased risk of prostate cancer and may provide a putative biomarker or epigenetic target for chemotherapeutics. Mechanistic studies are warranted to determine the role of the methylation marks in prostate cancer.
DOI: 10.6084/m9.figshare.12851669.v3
title: Expression of UDP Glucuronosyltransferases <i>2B15</i> and <i>2B17</i> is associated with methylation status in prostate cancer cells

description: Studies have suggested that abrogated expression of detoxification enzymes, UGT2B15 and UGT2B17, are associated with prostate tumour risk and progression. We investigated the role of EGF on the expression of these enzymes since it interacts with signalling pathways to also affect prostate tumour progression and is additionally associated with decreased DNA methylation. The expression of <i>UGT2B15, UGT2B17</i>, <i>de novo</i> methyltransferases, <i>DNMT3A</i> and <i>DNMT3B</i> was assessed in prostate cancer cells (LNCaP) treated with EGF, an EGFR inhibitor PD16893, and the methyltransferase inhibitor, 5-azacytidine, respectively. The results showed that EGF treatment decreased levels of expression of all four genes and that their expression was reversed by PD16893. Treatment with 5-azacytidine, markedly decreased expression of <i>UGT2B15</i> and <i>UGT2B17</i> over 85% as well as significantly decreased expression of <i>DNMT3B</i>, but not the expression of <i>DNMT3A. DNMT3B</i> siRNA treated LNCaP cells had decreased expression of <i>UGT2B15</i> and <i>UGT2B17</i>, while <i>DNMT3A</i> siRNA treated cells had only moderately decreased <i>UGT2B15</i> expression. Treatment with DNMT methyltransferase inhibitor, RG108, significantly decreased <i>UGT2B17</i> expression. Additionally, methylation differences between prostate cancer samples and benign prostate samples from an Illumina 450K Methylation Array study were assessed. The results taken together suggest that hypomethylation of the <i>UGT2B15</i> and <i>UGT2B17</i> genes contributes to increased risk of prostate cancer and may provide a putative biomarker or epigenetic target for chemotherapeutics. Mechanistic studies are warranted to determine the role of the methylation marks in prostate cancer.
DOI: 10.6084/m9.figshare.12851663.v3
title: Genome-wide DNA methylation differences and polychlorinated biphenyl (PCB) exposure in a US population

description: Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR &lt; 0.05). These CpGs were enriched in active promoter and transcription associated regions (p
DOI: 10.6084/m9.figshare.12851669.v2
title: Expression of UDP Glucuronosyltransferases <i>2B15</i> and <i>2B17</i> Is Associated with Methylation Status in Prostate Cancer cells

description: Studies have suggested that abrogated expression of detoxification enzymes, UGT2B15 and UGT2B17, are associated with prostate tumor risk and progression. We investigated the role of EGF on the expression of these enzymes since it interacts with signaling pathways to also affect prostate tumor progression and is additionally associated with decreased DNA methylation. The expression of <i>UGT2B15, UGT2B17</i>, de novo methyltransferases, <i>DNMT3A</i> and <i>DNMT3B</i> was assessed in prostate cancer cells (LNCaP) treated with EGF; an <i>EGFR</i> inhibitor PD16893 and the methyltransferase inhibitor, 5-azacytidine, respectively. The results showed that EGF treatment decreased levels of expression for all four genes and that expression was reversed by PD16893. Treatment with 5- azacytidine, markedly decreased expression of <i>UGT2B15</i> and <i>UGT2B17</i> over 85% as well as significantly decreased expression of <i>DNMT3B</i>, but not the expression of <i>DNMT3A. DNMT3B</i> siRNA treated LNCaP cells had decreased expression for <i>UGT2B15</i> and <i>UGT2B17</i>, while <i>DNMT3A</i> siRNA treated cells only moderately decreased <i>UGT2B15</i> expression. Treatment with DNMT methyltransferase inhibitor, RG108 significantly decreased <i>UGT2B17</i> expression. Additionally, methylation differences between prostate cancer samples and benign prostate samples from an Illumina 450K Methylation Array study were assessed. The results taken together suggest that hypomethylation of the <i>UGT2B15</i> and <i>UGT2B17</i> genes contributes to increased risk of prostate cancer and may provide a putative biomarker or epigenetic target for chemotherapeutics. Mechanistic studies are warranted to determine the role of the methylation marks in prostate cancer.
DOI: 10.6084/m9.figshare.11918181.v1
title: A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML

description: Translocations of the <i>KMT2A</i> (MLL) gene define a biologically distinct and clinically aggressive subtype of acute myeloid leukaemia (AML), marked by a characteristic gene expression profile and few cooperating mutations. Although dysregulation of the epigenetic landscape in this leukaemia is particularly interesting given the low mutation frequency, its comprehensive analysis using whole genome bisulphite sequencing (WGBS) has not been previously performed. Here we investigated epigenetic dysregulation in nine MLL-rearranged (MLL-r) AML samples by comparing them to six normal myeloid controls, using a computational method that encapsulates mean DNA methylation measurements along with analyses of methylation stochasticity. We discovered a dramatically altered epigenetic profile in MLL-r AML, associated with genome-wide hypomethylation and a markedly increased DNA methylation entropy reflecting an increasingly disordered epigenome. Methylation discordance mapped to key genes and regulatory elements that included bivalent promoters and active enhancers. Genes associated with significant changes in methylation stochasticity recapitulated known MLL-r AML expression signatures, suggesting a role for the altered epigenetic landscape in the transcriptional programme initiated by MLL translocations. Accordingly, we established statistically significant associations between discordances in methylation stochasticity and gene expression in MLL-r AML, thus providing a link between the altered epigenetic landscape and the phenotype.
DOI: 10.6084/m9.figshare.11918181
title: A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML

description: Translocations of the <i>KMT2A</i> (MLL) gene define a biologically distinct and clinically aggressive subtype of acute myeloid leukaemia (AML), marked by a characteristic gene expression profile and few cooperating mutations. Although dysregulation of the epigenetic landscape in this leukaemia is particularly interesting given the low mutation frequency, its comprehensive analysis using whole genome bisulphite sequencing (WGBS) has not been previously performed. Here we investigated epigenetic dysregulation in nine MLL-rearranged (MLL-r) AML samples by comparing them to six normal myeloid controls, using a computational method that encapsulates mean DNA methylation measurements along with analyses of methylation stochasticity. We discovered a dramatically altered epigenetic profile in MLL-r AML, associated with genome-wide hypomethylation and a markedly increased DNA methylation entropy reflecting an increasingly disordered epigenome. Methylation discordance mapped to key genes and regulatory elements that included bivalent promoters and active enhancers. Genes associated with significant changes in methylation stochasticity recapitulated known MLL-r AML expression signatures, suggesting a role for the altered epigenetic landscape in the transcriptional programme initiated by MLL translocations. Accordingly, we established statistically significant associations between discordances in methylation stochasticity and gene expression in MLL-r AML, thus providing a link between the altered epigenetic landscape and the phenotype.
DOI: 10.6084/m9.figshare.12851663.v2
title: Genome-wide DNA methylation differences and polychlorinated biphenyl (PCB) exposure in a US population

description: Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR &lt; 0.05). These CpGs were enriched in active promoter and transcription associated regions (p &lt; 0.05), and in regions around the binding sites for transcription factors involved in xenobiotic metabolism and immune function (FDR &lt; 0.05). PCB exposure also associated with proportions of CD4T, NK, and granulocyte cell types, and with the neutrophil to lymphocyte ratio (NLR) (p &lt; 0.05), and the estimated effect sizes of PCB on the epigenome were correlated with the effect sizes previously reported in an epigenome-wide study of C-reactive protein (r = 0.29; p = 2.22e-5), supporting previous studies on the association between PCB and immune dysfunction. These results indicate that PCB exposure is associated with differences in epigenetic marks in active regions of the genome, and future work should investigate whether these may mediate the association between PCB and health consequences.
DOI: 10.6084/m9.figshare.11806509
title: CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain

description: The Presenilin1 (<i>PSEN1</i>) gene encodes the catalytic peptide of the γ-secretase complex, a key enzyme that cleaves the amyloid-β protein precursor (AβPP), to generate the amyloid-β (Aβ) peptides, involved in Alzheimer’s Disease (AD). Other substrates of the γ-secretase, such as E-cadherin and Notch1, are involved in neurodevelopment and haematopoiesis. Gene-specific DNA methylation influences <i>PSEN1</i> expression in AD animal models. Here we evaluated canonical and non-canonical cytosine methylation patterns of the <i>PSEN1</i> 5ʹ-flanking during brain development and AD progression, in DNA extracted from the frontal cortex of AD transgenic mice (TgCRND8) and post-mortem human brain. Mapping CpG and non-CpG methylation revealed different methylation profiles in mice and humans. <i>PSEN1</i> expression only correlated with DNA methylation in adult female mice. However, in post-mortem human brain, lower methylation, both at CpG and non-CpG sites, correlated closely with higher <i>PSEN1</i> expression during brain development and in disease progression. <i>PSEN1</i> methylation in blood DNA was significantly lower in AD patients than in controls. The present study is the first to demonstrate a temporal correlation between dynamic changes in <i>PSEN1</i> CpG and non-CpG methylation patterns and mRNA expression during neurodevelopment and AD neurodegeneration. These observations were made possible by the use of an improved bisulphite methylation assay employing primers that are not biased towards non-CpG methylation. Our findings deepen the understanding of γ-secretase regulation and support the hypothesis that epigenetic changes can promote the pathophysiology of AD. Moreover, they suggest that <i>PSEN1</i> DNA methylation in peripheral blood may provide a biomarker for AD.
DOI: 10.6084/m9.figshare.11854692
title: Developmental genome-wide DNA methylation asymmetry between mouse placenta and embryo

description: In early embryos, DNA methylation is remodelled to initiate the developmental program but for mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution DNA methylation maps of mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryonic and placental DNA methylation patterns. We show that the asymmetry occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri–implantation stages, the <i>de novo</i> methyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially compensate in the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principal <i>de novo</i> methyltransferase, the compensatory DNA methylation mechanism of DNMT3B on DMRs becomes less effective.
DOI: 10.6084/m9.figshare.11806509.v1
title: CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain

description: The Presenilin1 (<i>PSEN1</i>) gene encodes the catalytic peptide of the γ-secretase complex, a key enzyme that cleaves the amyloid-β protein precursor (AβPP), to generate the amyloid-β (Aβ) peptides, involved in Alzheimer’s Disease (AD). Other substrates of the γ-secretase, such as E-cadherin and Notch1, are involved in neurodevelopment and haematopoiesis. Gene-specific DNA methylation influences <i>PSEN1</i> expression in AD animal models. Here we evaluated canonical and non-canonical cytosine methylation patterns of the <i>PSEN1</i> 5ʹ-flanking during brain development and AD progression, in DNA extracted from the frontal cortex of AD transgenic mice (TgCRND8) and post-mortem human brain. Mapping CpG and non-CpG methylation revealed different methylation profiles in mice and humans. <i>PSEN1</i> expression only correlated with DNA methylation in adult female mice. However, in post-mortem human brain, lower methylation, both at CpG and non-CpG sites, correlated closely with higher <i>PSEN1</i> expression during brain development and in disease progression. <i>PSEN1</i> methylation in blood DNA was significantly lower in AD patients than in controls. The present study is the first to demonstrate a temporal correlation between dynamic changes in <i>PSEN1</i> CpG and non-CpG methylation patterns and mRNA expression during neurodevelopment and AD neurodegeneration. These observations were made possible by the use of an improved bisulphite methylation assay employing primers that are not biased towards non-CpG methylation. Our findings deepen the understanding of γ-secretase regulation and support the hypothesis that epigenetic changes can promote the pathophysiology of AD. Moreover, they suggest that <i>PSEN1</i> DNA methylation in peripheral blood may provide a biomarker for AD.