cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.21341360.v1
title: Epigenetic mechanisms underlying the association between maternal climate stress and child growth: characterizing severe drought and its impact on a Kenyan community engaging in a climate change-sensitive livelihood

description: Pastoralists in East Africa are among the world’s most vulnerable communities to climate change, already living near their upper thermal limits and engaging in a climate-sensitive livelihood in a climate change global hot spot. Pregnant women and children are even more at risk. Here, we report the findings of a study characterizing Samburu pastoralist women’s experiences of severe drought and outcomes in their children (N = 213, 1.8–9.6 y). First, we examined potential DNA methylation (DNAm) differences between children exposed to severe drought in utero and same-sex unexposed siblings. Next, we performed a high-dimensional mediation analysis to test whether DNAm mediated associations of exposure to severe drought with body weight and adiposity. DNAm was measured using the Infinium MethylationEPIC BeadChip array. After quality control; batch, chip, and genomic inflation corrections; covariate adjustment; and multiple testing correction, 16 CpG sites were differentially methylated between exposed and unexposed children, predominantly in metabolism and immune function pathways. We found a significant indirect effect of drought exposure on child body weight through cg03771070. Our results are the first to identify biological mediators linking severe drought to child growth in a low-income global hot spot for climate change. A better understanding of the mechanisms underlying the association between drought exposure and child growth is important to increasing climate change resilience by identifying targets for intervention. For pregnant women in populations engaging in climate-sensitive livelihoods, severe drought is characterized by multiple stressors, including intense, sometimes hazardous labour, food and water insecurity, and other stressors. This study found differential methylation between children exposed to severe drought in utero versus their unexposed same-sex siblings in 16 CpG sites in pathways relevant to the immune system and metabolism. Cg03771070 was found to mediate the association between severe drought exposure and child body weight. The necessary next step includes context-nuanced prospective studies to further refine our understanding of biological mechanisms for climate-associated child outcomes. This is necessary for targeted interventions to improve climate change resilience in these communities.
DOI: 10.6084/m9.figshare.20651975
title: Epigenome-wide association studies of occupational exposure to benzene and formaldehyde

description: Sufficient evidence supports a relationship between certain myeloid neoplasms and exposure to benzene or formaldehyde. DNA methylation could underlie benzene- and formaldehyde-induced health outcomes, but data in exposed human populations are limited. We conducted two cross-sectional epigenome-wide association studies (EWAS), one in workers exposed to benzene and another in workers exposed to formaldehyde. Using HumanMethylation450 BeadChips, we investigated differences in blood cell DNA methylation among 50 benzene-exposed subjects and 48 controls, and among 31 formaldehyde-exposed subjects and 40 controls. We performed CpG-level and regional-level analyses. In the benzene EWAS, we found genome-wide significant alterations, i.e., FWER-controlled <i>P</i>-values &lt;0.05, in the mean and variance of methylation at 22 and 318 CpG sites, respectively, and in mean methylation of a large genomic region. Pathway analysis of genes corresponding to benzene-associated differential methylation sites revealed an impact on the AMPK signalling pathway. In formaldehyde-exposed subjects compared to controls, 9 CpGs in the <i>DUSP22</i> gene promoter had genome-wide significant decreased methylation variability and a large region of the <i>HOXA5</i> promoter with 44 CpGs was hypomethylated. Our findings suggest that DNA methylation may contribute to the pathogenesis of diseases related to benzene and formaldehyde exposure. Aberrant expression and methylation of <i>HOXA5</i> previously has been shown to be clinically significant in myeloid leukaemias. The tumour suppressor gene <i>DUSP22</i> is a potential biomarker of exposure to formaldehyde, and irregularities have been associated with multiple exposures and diseases.
DOI: 10.6084/m9.figshare.20651975.v1
title: Epigenome-wide association studies of occupational exposure to benzene and formaldehyde

description: Sufficient evidence supports a relationship between certain myeloid neoplasms and exposure to benzene or formaldehyde. DNA methylation could underlie benzene- and formaldehyde-induced health outcomes, but data in exposed human populations are limited. We conducted two cross-sectional epigenome-wide association studies (EWAS), one in workers exposed to benzene and another in workers exposed to formaldehyde. Using HumanMethylation450 BeadChips, we investigated differences in blood cell DNA methylation among 50 benzene-exposed subjects and 48 controls, and among 31 formaldehyde-exposed subjects and 40 controls. We performed CpG-level and regional-level analyses. In the benzene EWAS, we found genome-wide significant alterations, i.e., FWER-controlled <i>P</i>-values &lt;0.05, in the mean and variance of methylation at 22 and 318 CpG sites, respectively, and in mean methylation of a large genomic region. Pathway analysis of genes corresponding to benzene-associated differential methylation sites revealed an impact on the AMPK signalling pathway. In formaldehyde-exposed subjects compared to controls, 9 CpGs in the <i>DUSP22</i> gene promoter had genome-wide significant decreased methylation variability and a large region of the <i>HOXA5</i> promoter with 44 CpGs was hypomethylated. Our findings suggest that DNA methylation may contribute to the pathogenesis of diseases related to benzene and formaldehyde exposure. Aberrant expression and methylation of <i>HOXA5</i> previously has been shown to be clinically significant in myeloid leukaemias. The tumour suppressor gene <i>DUSP22</i> is a potential biomarker of exposure to formaldehyde, and irregularities have been associated with multiple exposures and diseases.
DOI: 10.6084/m9.figshare.20767335
title: m<i>ir152</i> hypomethylation as a mechanism for non-syndromic cleft lip and palate

description: Non-syndromic cleft lip with or without cleft palate (NSCLP), the most common human craniofacial malformation, is a complex disorder given its genetic heterogeneity and multifactorial component revealed by genetic, epidemiological, and epigenetic findings. Epigenetic variations associated with NSCLP have been identified; however, functional investigation has been limited. Here, we combined a reanalysis of NSCLP methylome data with genetic analysis and used both <i>in vitro</i> and <i>in vivo</i> approaches to dissect the functional effects of epigenetic changes. We found a region in <i>mir152</i> that is frequently hypomethylated in NSCLP cohorts (21–26%), leading to <i>mir152</i> overexpression. <i>mir152</i> overexpression in human neural crest cells led to downregulation of spliceosomal, ribosomal, and adherens junction genes. <i>In vivo</i> analysis using zebrafish embryos revealed that <i>mir152</i> upregulation leads to craniofacial cartilage impairment. Also, we suggest that zebrafish embryonic hypoxia leads to <i>mir152</i> upregulation combined with <i>mir152</i> hypomethylation and also analogous palatal alterations. We therefore propose that <i>mir152</i> hypomethylation, potentially induced by hypoxia in early development, is a novel and frequent predisposing factor to NSCLP.
DOI: 10.6084/m9.figshare.20767335.v1
title: m<i>ir152</i> hypomethylation as a mechanism for non-syndromic cleft lip and palate

description: Non-syndromic cleft lip with or without cleft palate (NSCLP), the most common human craniofacial malformation, is a complex disorder given its genetic heterogeneity and multifactorial component revealed by genetic, epidemiological, and epigenetic findings. Epigenetic variations associated with NSCLP have been identified; however, functional investigation has been limited. Here, we combined a reanalysis of NSCLP methylome data with genetic analysis and used both <i>in vitro</i> and <i>in vivo</i> approaches to dissect the functional effects of epigenetic changes. We found a region in <i>mir152</i> that is frequently hypomethylated in NSCLP cohorts (21–26%), leading to <i>mir152</i> overexpression. <i>mir152</i> overexpression in human neural crest cells led to downregulation of spliceosomal, ribosomal, and adherens junction genes. <i>In vivo</i> analysis using zebrafish embryos revealed that <i>mir152</i> upregulation leads to craniofacial cartilage impairment. Also, we suggest that zebrafish embryonic hypoxia leads to <i>mir152</i> upregulation combined with <i>mir152</i> hypomethylation and also analogous palatal alterations. We therefore propose that <i>mir152</i> hypomethylation, potentially induced by hypoxia in early development, is a novel and frequent predisposing factor to NSCLP.
DOI: 10.6084/m9.figshare.20155792
title: Epigenetic rewiring of pathways related to odour perception in immune cells exposed to SARS-CoV-2 <i>in vivo</i> and <i>in vitro</i>

description: A majority of SARS-CoV-2 recoverees develop only mild-to-moderate symptoms, while some remain completely asymptomatic. Although viruses, including SARS-CoV-2, may evade host immune responses by epigenetic mechanisms including DNA methylation, little is known about whether these modifications are important in defence against and healthy recovery from COVID-19 in the host. To this end, epigenome-wide DNA methylation patterns from COVID-19 convalescents were compared to uninfected controls from before and after the pandemic. Peripheral blood mononuclear cell (PBMC) DNA was extracted from uninfected controls, COVID-19 convalescents, and symptom-free individuals with SARS-CoV-2-specific T cell-responses, as well as from PBMCs stimulated <i>in vitro</i> with SARS-CoV-2. Subsequently, the Illumina MethylationEPIC 850K array was performed, and statistical/bioinformatic analyses comprised differential DNA methylation, pathway over-representation, and module identification analyses. Differential DNA methylation patterns distinguished COVID-19 convalescents from uninfected controls, with similar results in an experimental SARS-CoV-2 infection model. A SARS-CoV-2-induced module was identified <i>in vivo</i>, comprising 66 genes of which six (<i>TP53, INS, HSPA4, SP1, ESR1,</i> and <i>FAS</i>) were present in corresponding <i>in vitro</i> analyses. Over-representation analyses revealed involvement in Wnt, muscarinic acetylcholine receptor signalling, and gonadotropin-releasing hormone receptor pathways. Furthermore, numerous differentially methylated and network genes from both settings interacted with the SARS-CoV-2 interactome. Altered DNA methylation patterns of COVID-19 convalescents suggest recovery from mild-to-moderate SARS-CoV-2 infection leaves longstanding epigenetic traces. Both <i>in vitro</i> and <i>in vivo</i> exposure caused epigenetic modulation of pathways thataffect odour perception. Future studies should determine whether this reflects host-induced protective antiviral defense or targeted viral hijacking to evade host defence.
DOI: 10.6084/m9.figshare.20155792.v1
title: Epigenetic rewiring of pathways related to odour perception in immune cells exposed to SARS-CoV-2 <i>in vivo</i> and <i>in vitro</i>

description: A majority of SARS-CoV-2 recoverees develop only mild-to-moderate symptoms, while some remain completely asymptomatic. Although viruses, including SARS-CoV-2, may evade host immune responses by epigenetic mechanisms including DNA methylation, little is known about whether these modifications are important in defence against and healthy recovery from COVID-19 in the host. To this end, epigenome-wide DNA methylation patterns from COVID-19 convalescents were compared to uninfected controls from before and after the pandemic. Peripheral blood mononuclear cell (PBMC) DNA was extracted from uninfected controls, COVID-19 convalescents, and symptom-free individuals with SARS-CoV-2-specific T cell-responses, as well as from PBMCs stimulated <i>in vitro</i> with SARS-CoV-2. Subsequently, the Illumina MethylationEPIC 850K array was performed, and statistical/bioinformatic analyses comprised differential DNA methylation, pathway over-representation, and module identification analyses. Differential DNA methylation patterns distinguished COVID-19 convalescents from uninfected controls, with similar results in an experimental SARS-CoV-2 infection model. A SARS-CoV-2-induced module was identified <i>in vivo</i>, comprising 66 genes of which six (<i>TP53, INS, HSPA4, SP1, ESR1,</i> and <i>FAS</i>) were present in corresponding <i>in vitro</i> analyses. Over-representation analyses revealed involvement in Wnt, muscarinic acetylcholine receptor signalling, and gonadotropin-releasing hormone receptor pathways. Furthermore, numerous differentially methylated and network genes from both settings interacted with the SARS-CoV-2 interactome. Altered DNA methylation patterns of COVID-19 convalescents suggest recovery from mild-to-moderate SARS-CoV-2 infection leaves longstanding epigenetic traces. Both <i>in vitro</i> and <i>in vivo</i> exposure caused epigenetic modulation of pathways thataffect odour perception. Future studies should determine whether this reflects host-induced protective antiviral defense or targeted viral hijacking to evade host defence.
DOI: 10.6084/m9.figshare.20391435
title: Long non-coding RNA <i>Gm10561</i> promotes myogenesis by sponging miR-432

description: Skeletal myogenesis is a highly ordered process finely regulated by various factors. Long non-coding RNAs play an important regulatory role in myogenesis via multiple mechanisms. In this study, we identified the lncRNA <i>Gm10561</i>, which was upregulated during myogenic differentiation and is highly expressed in skeletal muscle. Knockdown of <i>Gm10561</i> inhibited the proliferation and differentiation of C2C12 myoblasts <i>in vitro</i> and muscle growth <i>in vivo</i>. Overexpression of <i>Gm10561</i> promoted the proliferation and differentiation of both C2C12 myoblasts and porcine muscle satellite cells. Notably, lncRNA <i>Gm10561</i> is localized in the cytoplasm and competitively bound to miR-432, which directly targets <i>MEF2C</i> and <i>E2F3</i>. It was confirmed that lncRNA <i>Gm10561</i> regulates the proliferation and differentiation of myoblasts by acting as a sponge of miR-432 to modulate <i>MEF2C</i> and <i>E2F3</i> expression. Thus, the lncRNA-<i>Gm10561</i>-miR-432-<i>MEF2C</i>/<i>E2F3</i> axis plays an important role in myogenesis.
DOI: 10.6084/m9.figshare.20391435.v1
title: Long non-coding RNA <i>Gm10561</i> promotes myogenesis by sponging miR-432

description: Skeletal myogenesis is a highly ordered process finely regulated by various factors. Long non-coding RNAs play an important regulatory role in myogenesis via multiple mechanisms. In this study, we identified the lncRNA <i>Gm10561</i>, which was upregulated during myogenic differentiation and is highly expressed in skeletal muscle. Knockdown of <i>Gm10561</i> inhibited the proliferation and differentiation of C2C12 myoblasts <i>in vitro</i> and muscle growth <i>in vivo</i>. Overexpression of <i>Gm10561</i> promoted the proliferation and differentiation of both C2C12 myoblasts and porcine muscle satellite cells. Notably, lncRNA <i>Gm10561</i> is localized in the cytoplasm and competitively bound to miR-432, which directly targets <i>MEF2C</i> and <i>E2F3</i>. It was confirmed that lncRNA <i>Gm10561</i> regulates the proliferation and differentiation of myoblasts by acting as a sponge of miR-432 to modulate <i>MEF2C</i> and <i>E2F3</i> expression. Thus, the lncRNA-<i>Gm10561</i>-miR-432-<i>MEF2C</i>/<i>E2F3</i> axis plays an important role in myogenesis.
DOI: 10.6084/m9.figshare.20473069
title: Maternal high-fat diet modifies epigenetic marks H3K27me3 and H3K27ac in bone to regulate offspring osteoblastogenesis in mice

description: Studies from both humans and animal models indicated that maternal chronic poor-quality diet, especially a high fat diet (HFD), is significantly associated with reduced bone density and childhood fractures in offspring. When previously studied in a rat model, our data suggested that maternal HFD changes epigenetic marks such as DNA methylation and histone modifications to control osteoblast metabolism. In mouse embryonic and postnatal offspring bone samples, a ChIP-sequencing (ChIP-Seq)-based genome-wide method was used to locate the repressive histone mark H3K27me3 (mediated via the polycomb histone methyltransferase, <i>Ezh2</i>) and expressive histone mark H3K27ac (<i>p300/CBP</i> mediated) throughout the genome. Using isolated mouse embryonic cells from foetal calvaria (osteoblast-like cells), H3K27me3 ChIP-Seq showed that 147 gene bodies and 26 gene promoters in HFD embryotic samples had a greater than twofold increase in H3K27me peaks compared to controls. Among the HFD samples, <i>Pthlh</i> and <i>Col2a1</i> that are important genes playing roles during chondro- and osteogenesis had significantly enriched levels of H3K27me3. Their decreased mRNA expression was confirmed by real-time PCR and standard ChIP analysis, indicating a strong association with <i>Ezh2</i> mediated H3K27me3 epigenetic changes. Using embryonic calvaria osteoblastic cells and offspring bone samples, H3K27ac ChIP-Seq analysis showed that osteoblast inhibitor genes <i>Tnfaip3</i> and <i>Twist1</i> had significantly enriched peaks of H3K27ac in HFD samples compared to controls. Their increased gene expression and association with H3K27ac were also confirmed by real-time PCR and standard ChIP analysis. These findings indicate that chronic maternal HFD changes histone trimethylation and acetylation epigenetic marks to regulate expression of genes controlling osteoblastogenesis.
DOI: 10.6084/m9.figshare.20473069.v1
title: Maternal high-fat diet modifies epigenetic marks H3K27me3 and H3K27ac in bone to regulate offspring osteoblastogenesis in mice

description: Studies from both humans and animal models indicated that maternal chronic poor-quality diet, especially a high fat diet (HFD), is significantly associated with reduced bone density and childhood fractures in offspring. When previously studied in a rat model, our data suggested that maternal HFD changes epigenetic marks such as DNA methylation and histone modifications to control osteoblast metabolism. In mouse embryonic and postnatal offspring bone samples, a ChIP-sequencing (ChIP-Seq)-based genome-wide method was used to locate the repressive histone mark H3K27me3 (mediated via the polycomb histone methyltransferase, <i>Ezh2</i>) and expressive histone mark H3K27ac (<i>p300/CBP</i> mediated) throughout the genome. Using isolated mouse embryonic cells from foetal calvaria (osteoblast-like cells), H3K27me3 ChIP-Seq showed that 147 gene bodies and 26 gene promoters in HFD embryotic samples had a greater than twofold increase in H3K27me peaks compared to controls. Among the HFD samples, <i>Pthlh</i> and <i>Col2a1</i> that are important genes playing roles during chondro- and osteogenesis had significantly enriched levels of H3K27me3. Their decreased mRNA expression was confirmed by real-time PCR and standard ChIP analysis, indicating a strong association with <i>Ezh2</i> mediated H3K27me3 epigenetic changes. Using embryonic calvaria osteoblastic cells and offspring bone samples, H3K27ac ChIP-Seq analysis showed that osteoblast inhibitor genes <i>Tnfaip3</i> and <i>Twist1</i> had significantly enriched peaks of H3K27ac in HFD samples compared to controls. Their increased gene expression and association with H3K27ac were also confirmed by real-time PCR and standard ChIP analysis. These findings indicate that chronic maternal HFD changes histone trimethylation and acetylation epigenetic marks to regulate expression of genes controlling osteoblastogenesis.
DOI: 10.6084/m9.figshare.20523820
title: Gestational diabetes mellitus placentas exhibit epimutations at placental development genes

description: Gestational diabetes mellitus (GDM) is a maternal metabolic disorder that perturbs placental development and increases the risk of offspring short- and long-term metabolic disorders. The mechanisms by which GDM impairs placental development remain poorly understood. Here, we defined the DNA methylome of GDM placentas and determined whether GDM perturbs methylation at genes important for placental development. We conducted an epigenome-wide association study of 42 placentas from pregnancies in the South African Soweto First 1000 days cohort (S1000). Using genome-wide bisulfite sequencing, we compared non-GDM placentas to GDM placentas with similar proportions from obese and non-obese mothers. Compared to non-GDM, GDM placentas exhibited a distinct methylation profile consisting of 12,210 differentially methylated CpGs (DMCs) that mapped to 3,875 genes. Epigenetically altered genes were enriched in Wnt and cadherin signalling pathways, both critical in placentation and embryogenesis. We also defined regional DNA methylation perturbation in GDM placentas at 11 placental development genes. These findings reveal extensive changes to the placental epigenome of GDM pregnancies and highlight perturbation enriched at important placental development genes. These molecular changes represent potential mechanisms for GDM-induced placental effects that may serve as candidate biomarkers for placental, maternal, and foetal health. Using a study design that used similar proportions of obese and non-obese mothers in our case and control pregnancies, we minimized the detection of changes due to obesity alone. Further work will be necessary to investigate the extent of the influence of obesity on these GDM-related placental epigenetic changes.
DOI: 10.6084/m9.figshare.21196420
title: Prenatal lead (Pb) exposure is associated with differential placental DNA methylation and hydroxymethylation in a human population

description: Prenatal lead (Pb) exposure is associated with adverse developmental outcomes and to epigenetic alterations such as DNA methylation and hydroxymethylation in animal models and in newborn blood. Given the importance of the placenta in foetal development, we sought to examine how prenatal Pb exposure was associated with differential placental DNA methylation and hydroxymethylation and to identify affected biological pathways linked to developmental outcomes. Maternal (n = 167) and infant (n = 172) toenail and placenta (n = 115) samples for prenatal Pb exposure were obtained from participants in a US birth cohort, and methylation and hydroxymethylation data were quantified using the Illumina Infinium MethylationEPIC BeadChip. An epigenome-wide association study was applied to identify differential methylation and hydroxymethylation associated with Pb exposure. Biological functions of the Pb-associated genes were determined by overrepresentation analysis through ConsensusPathDB. Prenatal Pb quantified from maternal toenail, infant toenail, and placenta was associated with 480, 27, and 2 differentially methylated sites (q &lt; 0.05), respectively, with both increases and decreases associated with exposure. Alternatively, we identified 2, 1, and 14 differentially hydroxymethylated site(s) associated with maternal toenail, infant toenail, and placental Pb, respectively, with most showing increases in hydroxymethylation with exposure. Significantly overrepresented pathways amongst genes associated with differential methylation and hydroxymethylation (q &lt; 0.10) included mechanisms pertaining to nervous system and organ development, calcium transport and regulation, and signalling activities. Our results suggest that both methylation and hydroxymethylation in the placenta can be variable based on Pb exposure and that the pathways impacted could affect placental function.