DNA Methylation Explains a Subset of Placental Gene Expression Differences Based on Ancestry and Altitude

Abstract:Objectives: The most pronounced effect of high altitude (>2700m) on reproductive outcomes is reduced birth weight. Indigenous Bolivians (Andean Native Americans) residing for generations at high altitudes have higher birth weights relative to more recent migrants of primarily European ancestry. Previous research demonstrated that the placenta is a key contributor to the preservation of Andean birth weight at high altitude. Our current research investigated how gene expression and epigenetics contributes to the conservation of birth weight at high altitude by examining mRNA expression and DNA methylation differences between placentas of Andeans and those of European ancestry residing at high and low altitude.Methods: Genome-wide mRNA expression and DNA methylation of villous placenta tissue was quantified utilizing microarray technology. Subjects were of Andean and European ancestry and resident at high (3600m) or low (400m) altitudes. Differentially expressed genes (DEGs) associated with altitude or ancestry were identified (FDR<0.1, |fold change|>1.25). To predict which DEGs could be regulated by methylation we tested for correlation between gene expression and methylation values.Results: 69 DEGs associated with altitude (n=36) or ancestry (n=34) were identified. Altitude-associated DEGs included members of the AP-1 transcription factor family. Ancestry-associated DEGs were implicated in inflammatory pathways and associated with pro-angiogenic macrophages. More ancestry-associated DEGs correlated significantly (n=17) (FDR<0.1) with promoter or gene body methylation (p=0.0242) when compared to altitude associated DEGs (n=8).Conclusions:Compared to altitude-associated DEGs, methylation regulates more ancestry-associated DEGs, potentially allowing for rapid modification in the expression of inflammatory genes to attract pro-angiogenic macrophages as a means of promoting placental capillary growth in Andeans, regardless of altitude.

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DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽

10.2217/epi-2021-0006 ◽

2021 ◽

Author(s):

Beatriz Garcia-Ruiz ◽

Manuel Castro de Moura ◽

Gerard Muntané ◽

Lourdes Martorell ◽

Elena Bosch ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Bipolar Disorder ◽

Mrna Expression ◽

Gene Expression Analysis ◽

Mrna Levels ◽

Healthy Controls ◽

Genome Wide ◽

Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

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Phylogenetic Shifts in Gene Body Methylation Correlate with Gene Expression and Reflect Trait Conservation

Molecular Biology and Evolution ◽

10.1093/molbev/msz195 ◽

2019 ◽

Vol 37 (1) ◽

pp. 31-43 ◽

Cited By ~ 3

Author(s):

Danelle K Seymour ◽

Brandon S Gaut

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Molecular Evolution ◽

Methylation Status ◽

Evolutionary Constraint ◽

Gene Body ◽

Gene Body Methylation ◽

Plant Genomes ◽

Genome Wide ◽

Rates Of Molecular Evolution

Abstract A subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.

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Genome-Wide DNA Methylation Changes Associated With High-Altitude Acclimatization During an Everest Base Camp Trek

Frontiers in Physiology ◽

10.3389/fphys.2021.660906 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ainash Childebayeva ◽

Taylor Harman ◽

Julien Weinstein ◽

Trevor Day ◽

Tom D. Brutsaert ◽

...

Keyword(s):

Dna Methylation ◽

High Altitude ◽

Stem Cell Differentiation ◽

European Ancestry ◽

Epigenetic Changes ◽

Short Term ◽

Altitude Acclimatization ◽

Genome Wide ◽

Base Camp ◽

High Altitude Acclimatization

The individual physiological response to high-altitude hypoxia involves both genetic and non-genetic factors, including epigenetic modifications. Epigenetic changes in hypoxia factor pathway (HIF) genes are associated with high-altitude acclimatization. However, genome-wide epigenetic changes that are associated with short-term hypoxia exposure remain largely unknown. We collected a series of DNA samples from 15 participants of European ancestry trekking to Everest Base Camp to identify DNA methylation changes associated with incremental altitude ascent. We determined genome-wide DNA methylation levels using the Illumina MethylationEPIC chip comparing two altitudes: baseline 1,400 m (day 0) and elevation 4,240 m (day 7). The results of our epigenome-wide association study revealed 2,873 significant differentially methylated positions (DMPs) and 361 significant differentially methylated regions (DMRs), including significant positions and regions in hypoxia inducible factor (HIF) and the renin–angiotensin system (RAS) pathways. Our pathway enrichment analysis identified 95 significant pathways including regulation of glycolytic process (GO:0006110), regulation of hematopoietic stem cell differentiation (GO:1902036), and regulation of angiogenesis (GO:0045765). Lastly, we identified an association between the ACE gene insertion/deletion (I/D) polymorphism and oxygen saturation, as well as average ACE methylation. These findings shed light on the genes and pathways experiencing the most epigenetic change associated with short-term exposure to hypoxia.

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Phylogenetic shifts in gene body methylation correlate with gene expression and reflect trait conservation

10.1101/687186 ◽

2019 ◽

Cited By ~ 1

Author(s):

Danelle K. Seymour ◽

Brandon S. Gaut

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Molecular Evolution ◽

Methylation Status ◽

Evolutionary Constraint ◽

Gene Body ◽

Gene Body Methylation ◽

Plant Genomes ◽

Genome Wide ◽

Rates Of Molecular Evolution

ABSTRACTA subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.

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Genome Wide Study of DNA Methylation In AML

Blood ◽

10.1182/blood.v116.21.3618.3618 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3618-3618

Author(s):

Marwa Saied ◽

Sabah Khaled ◽

Thomas Down ◽

Jacek Marzec ◽

Paul Smith ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Cpg Island ◽

Cpg Islands ◽

Differential Methylation ◽

Methylation Analysis ◽

Promoter Regions ◽

Gene Body Methylation ◽

Normal Bone ◽

Genome Wide

Abstract Abstract 3618 DNA methylation is the most stable epigenetic modification and has a major role in cancer initiation and progression. The two main aims for this research were, firstly, to use the genome wide analysis of DNA methylation to better understand the development of acute myeloid leukemia (AML). The second aim was to detect differentially methylated genes/regions between certain subtypes of AML and normal bone marrow (NBM). We used the methylated DNA immunoprecipitation technique followed by high-throughput sequencing by Illumina Genome Analyser II (MeDIP -seq) for 9 AML samples for which ethical approval has been obtained. The selected leukemias included three with the t(8; 21), three with the t(15; 17) translocations and three with normal karyotypes (NK). The control samples were 3 normal bone marrows (NBMs) from healthy donors. The number of reads generated from Illumina ranged between 18– 20 million paired-end reads/lane with a good base quality from both ends (base quality > 30 represented 75%-85% of reads). The reads were aligned using 2 algorithms (Maq and Bowtie) and the methylation analysis was performed by Batman software (Bayesian Tool for Methylation Analysis). The creation of this genome-wide methylation map for AML permits the examination of the patterns for key genetic elements. Investigation of the 35,072 promoter regions identified 80 genes, which showed a significant differential methylation levels in leukemic cases in comparison to NBM; consistently high methylation levels in leukaemia were detected in the promoters of 70 genes e.g. DPP6, ID4, DCC, whereas high methylation levels in NBM, lost in leukaemia was observed in 10 genes e.g. ATF4. For each AML subtype, we also identified significant differentially methylated promoter regions e.g. PAX1 for t(8; 21), GRM7 for t(15; 17), NPM2 for NK. An analysis of gene body methylation identified 49 genes with significantly higher methylation in AML in comparison to NBM e.g. MYOD1 and 31 genes with a higher methylation in NBMs than AML e.g. GNG8. A similar analysis of 23,600 CpG islands identified 400 CpG islands with significant differential methylation levels between leukaemia and NBMs (212 CpG islands were found to have significantly increased methylation in leukaemia and 188 CpG islands had significantly higher methylation in NBMs). The pattern of methylation in CpG island “shores” (2 KB from either side of each CpG island) has been investigated and 312 CpG island shores showed a higher methylation in leukaemia and 88 CpG shores had a significant increase methylation levels in NBMs. This genome wide methylation map has been validated by using direct bisulfite sequencing of the regions identified above (Spearman r= 0.8, P <0.0001) and also by using Illumina Infinium assay (Spearman r= 0.7 P <0.0001) which interrogates regions at single representative CpGs. Comparison of previous array based gene expression data with this methylation map revealed a significant negative correlation between promoter methylation and gene expression (Pearson r= -0.9, P< 0.0001) while, gene body methylation showed a small negative correlation with gene expression, that was found in genes of CpG density >3% (Pearson r= -0.3, P< 0.0001). Conclusion: we have established a high-resolution (100bp) map of DNA methylation in AML and thus identified a novel list of genes, which have significantly differential methylation levels in AML. Disclosures: No relevant conflicts of interest to declare.

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Short-Term Effects on Gene-Expression and on DNA-Methylation at the Genome-Wide Level of the Iberian Ham Intake and Compared With Orange Intake: A Crossover Randomized Trial

Current Developments in Nutrition ◽

10.1093/cdn/nzab050_004 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 937-937

Author(s):

Dolores Corella ◽

José Sorlí ◽

Eva Asensio ◽

Rocío Barragán ◽

Olga Portolés ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Randomized Trial ◽

Intervention Group ◽

Enrichment Analysis ◽

Differentially Expressed ◽

European Ancestry ◽

Pathway Enrichment Analysis ◽

Short Term ◽

Genome Wide

Abstract Objectives Diet regulates gene expression and methylation profiles by several mechanisms. However, studies analyzing the simultaneous effect of specific foods on gene-expression and DNA methylation at the genome-wide level are very scarce. Therefore our aims were: To study the short-term transcriptomics and epigenomcis effects at the genome-wide level of the Iberian ham intake compared with orange intake in the same subjects. Methods We carried out a cross-over randomized trial (registered at ISRCTN17906849) in 33 healhty volunteers (aged 18–50 years and 50% females) of European ancestry. After 12h fasting, participants were randomly allocated to eat 67.5 g of Iberian ham (100% pure iberian breed and 100% acorn fed) or 500 g of peeled oranges (Citrus reticulata) depening on the intervention group. After a washout period, subjects were crossed over to the alternate treatment arm. Blood samples were taken at 0-h and at 4-h to isolate DNA and RNA from leukocytes. A random sample of 16 participants was selected for omics analyses (gene expression with the. GeneChip Human Gene 2.0 ST Array, and the EPIC-Illumina array (850K) for methylation). Eight arrays (2 times and 2 treatments per 2 omics) were obtained for each participant. Differences in gene expression and methylation (4 h vs baseline) were analyzed for Iberian ham, oranges and combined. Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Results The top-ranked genes differentially expressed P < 1 × 10–5) after Iberian ham intake (4 h vs baseline) were PKBP5 and PICALM. Pantothenate and CoA biosyntesis and the JAK-STAT singaling pathways were the most significantly enriched (P < 5 × 10–7). After orange intake, the top-ranked differentially expressed genes (P < 5 × 10–6) were: SMAP2 and RHEB, the pathways being (P < 5 × 10–9): Cellular senescence and ABC transporters. We detected top-ranked methylated CpGs both for ham and oranges, resulting the Chemokine signaling pathway differentially methylated for oranges and in the Neurothrophine singaling pathway for Iberian ham intake. Comparative combined analysis revealed additional differences. Conclusions A short-term intake of Iberian ham or oranges results in differences in gene expression as well as in DNA-methylation. Funding Sources CIBEROBN-06/03/035, PROMETEO-17/2017 APOSTD/2019/136), P1–1B2013–54 and COGRUP/2016/06

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Use of integrative epigenetic and mRNA expression analyses to identify significantly changed genes and functional pathways in osteoarthritic cartilage

Bone and Joint Research ◽

10.1302/2046-3758.75.bjr-2017-0284.r1 ◽

2018 ◽

Vol 7 (5) ◽

pp. 343-350 ◽

Cited By ~ 6

Author(s):

A. He ◽

Y. Ning ◽

Y. Wen ◽

Y. Cai ◽

K. Xu ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Mrna Expression ◽

Expression Profiles ◽

Enrichment Analysis ◽

Signalling Pathway ◽

Pathway Enrichment Analysis ◽

Osteoarthritic Cartilage ◽

Pathway Enrichment ◽

Genome Wide

Aim Osteoarthritis (OA) is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control the expression of genes and are likely to regulate the OA transcriptome. We performed integrative genomic analyses to define methylation-gene expression relationships in osteoarthritic cartilage. Patients and Methods Genome-wide DNA methylation profiling of articular cartilage from five patients with OA of the knee and five healthy controls was conducted using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, California). Other independent genome-wide mRNA expression profiles of articular cartilage from three patients with OA and three healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Integrative pathway enrichment analysis of DNA methylation and mRNA expression profiles was performed using integrated analysis of cross-platform microarray and pathway software. Gene ontology (GO) analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Results We identified 1265 differentially methylated genes, of which 145 are associated with significant changes in gene expression, such as DLX5, NCOR2 and AXIN2 (all p-values of both DNA methylation and mRNA expression < 0.05). Pathway enrichment analysis identified 26 OA-associated pathways, such as mitogen-activated protein kinase (MAPK) signalling pathway (p = 6.25 × 10-4), phosphatidylinositol (PI) signalling system (p = 4.38 × 10-3), hypoxia-inducible factor 1 (HIF-1) signalling pathway (p = 8.63 × 10-3 pantothenate and coenzyme A (CoA) biosynthesis (p = 0.017), ErbB signalling pathway (p = 0.024), inositol phosphate (IP) metabolism (p = 0.025), and calcium signalling pathway (p = 0.032). Conclusion We identified a group of genes and biological pathwayswhich were significantly different in both DNA methylation and mRNA expression profiles between patients with OA and controls. These results may provide new clues for clarifying the mechanisms involved in the development of OA. Cite this article: A. He, Y. Ning, Y. Wen, Y. Cai, K. Xu, Y. Cai, J. Han, L. Liu, Y. Du, X. Liang, P. Li, Q. Fan, J. Hao, X. Wang, X. Guo, T. Ma, F. Zhang. Use of integrative epigenetic and mRNA expression analyses to identify significantly changed genes and functional pathways in osteoarthritic cartilage. Bone Joint Res 2018;7:343–350. DOI: 10.1302/2046-3758.75.BJR-2017-0284.R1.

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Shedding Light on the African Enigma: In Vitro Testing of Homo sapiens-Helicobacter pylori Coevolution

Microorganisms ◽

10.3390/microorganisms9020240 ◽

2021 ◽

Vol 9 (2) ◽

pp. 240

Author(s):

Bruno Cavadas ◽

Marina Leite ◽

Nicole Pedro ◽

Ana C. Magalhães ◽

Joana Melo ◽

...

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Host Response ◽

Homo Sapiens ◽

European Ancestry ◽

Genome Wide ◽

Expression Host ◽

H Pylori ◽

Human Ancestry

The continuous characterization of genome-wide diversity in population and case–cohort samples, allied to the development of new algorithms, are shedding light on host ancestry impact and selection events on various infectious diseases. Especially interesting are the long-standing associations between humans and certain bacteria, such as the case of Helicobacter pylori, which could have been strong drivers of adaptation leading to coevolution. Some evidence on admixed gastric cancer cohorts have been suggested as supporting Homo-Helicobacter coevolution, but reliable experimental data that control both the bacterium and the host ancestries are lacking. Here, we conducted the first in vitro coinfection assays with dual human- and bacterium-matched and -mismatched ancestries, in African and European backgrounds, to evaluate the genome wide gene expression host response to H. pylori. Our results showed that: (1) the host response to H. pylori infection was greatly shaped by the human ancestry, with variability on innate immune system and metabolism; (2) African human ancestry showed signs of coevolution with H. pylori while European ancestry appeared to be maladapted; and (3) mismatched ancestry did not seem to be an important differentiator of gene expression at the initial stages of infection as assayed here.

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