Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

AbstractIndonesia is the world’s fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10% of tested genes are differentially expressed between the islands of Mentawai (Sumatra) and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.7% of genes strongly correlating with nearby CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by very local environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.

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Changes in DNA Methylation in Response to 6-Benzylaminopurine Affect Allele-Specific Gene Expression in Populus tomentosa

10.20944/preprints202002.0038.v1 ◽

2020 ◽

Author(s):

Anran Xuan ◽

Yuepeng Song ◽

Chenhao Bu ◽

Panfei Chen ◽

Yousry A. El-Kassaby ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Expression Patterns ◽

Populus Tomentosa ◽

Differentially Expressed ◽

Specific Gene ◽

Snp Analysis ◽

Specific Gene Expression ◽

Genome Wide ◽

Allele Specific

The cytokinins play important roles in plant growth and development by regulating gene expression at genome wide level. DNA methylation is responsive to the external environment, but whether DNA methylation changes in response to cytokinin treatment to regulate gene expression is still unclear. Here, we used bisulfite sequencing and RNA sequencing to examine genome-wide DNA methylation and gene expression patterns in poplar (Populus tomentosa) after treatment with the synthetic cytokinin 6-benzylaminopurine (6-BA). We identified 566 significantly differentially methylated regions (DMRs) in response to 6-BA treatment. Transcriptome analysis showed that 501 protein-coding genes, 262 long non-coding RNAs, and 15,793 24-nt small interfering RNAs were differentially expressed under 6-BA treatment. Among these, 79% were differentially expressed between alleles in P. tomentosa. Combined DNA methylation and gene expression analysis demonstrated that DNA methylation plays an important role in regulating allele-specific gene expression. To further investigate the relationship between these 6-BA-responsive genes and phenotypic variation, we performed SNP analysis of 507 6-BA-responsive DMRs via re-sequencing using a natural population of P. tomentosa and identified 206 SNPs that were significantly associated with growth and wood properties. Association analysis indicated that 53% of loci with allele-specific expression had primarily dominant effects on poplar traits. Our comprehensive analyses of P. tomentosa DNA methylation and the regulation of allele-specific gene expression suggest that DNA methylation is an important regulator of imbalanced expression between allelic loci.

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Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

PLoS Genetics ◽

10.1371/journal.pgen.1008749 ◽

2020 ◽

Vol 16 (5) ◽

pp. e1008749 ◽

Cited By ~ 3

Author(s):

Heini M. Natri ◽

Katalina S. Bobowik ◽

Pradiptajati Kusuma ◽

Chelzie Crenna Darusallam ◽

Guy S. Jacobs ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Expression Patterns ◽

Genetic Ancestry ◽

Gene Expression Patterns ◽

Indonesian Archipelago ◽

Genome Wide

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Genome Wide DNA Methylation and Transcriptome Analysis in HSC Aging

Blood ◽

10.1182/blood.v118.21.2367.2367 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2367-2367

Author(s):

Mira Jeong ◽

Deqiang Sun ◽

Min Luo ◽

Aysegul Ergen ◽

Hongcang Gu ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Differentially Expressed ◽

Mouse Bone Marrow ◽

Rna Seq ◽

Differentiation Potential ◽

Hematopoietic Stem ◽

Exon Arrays ◽

Age Related ◽

Genome Wide

Abstract Abstract 2367 Hematopoietic stem cell (HSC) Aging is a complex process linked to number of changes in gene expression and functional decline of self-renewal and differentiation potential. While epigenetic changes have been implicated in HSC aging, little direct evidence has been generated. DNA methylation is one of the major underlying mechanisms associated with the regulation of gene expression, but changes in DNA methylation patterns with HSC aging have not been characterized. We hypothesize that revealing the genome-wide DNA methylation and transcriptome signatures will lead to a greater understanding of HSC aging. Here, we report the first genome-scale study of epigenomic dynamics during normal mouse HSC aging. We isolated SP-KSL-CD150+ HSC populations from 4, 12, 24 month-old mouse bone marrow and carried out genome-wide reduced representative bisulfite sequencing (RRBS) and identified aging-associated differentially methylated CpGs. Three biological samples were sequenced from each aging group and we obtained 30–40 million high-quality reads with over 30X total coverage on ∼1.1M CpG sites which gives us adequate statistical power to infer methylation ratios. Bisulfite conversion rate of non-CpG cytosines was >99%. We analyzed a variety of genomic features to find that CpG island promoters, gene bodies, 5'UTRs, and 3'UTRs generally were associated with hypermethylation in aging HSCs. Overall, out of 1,777 differentially methylated CpGs, 92.8% showed age-related hypermethylation and 7.2% showed age-related hypomethylation. Gene ontology analyses have revealed that differentially methylated CpGs were significantly enriched near genes associated with alternative splicing, DNA binding, RNA-binding, transcription regulation, Wnt signaling and pathways in cancer. Most interestingly, over 579 splice variants were detected as candidates for age-related hypermethylation (86%) and hypomethylation (14%) including Dnmt3a, Runx1, Pbx1 and Cdkn2a. To quantify differentially expressed RNA-transcripts across the entire transcriptome, we performed RNA-seq and analyzed exon arrays. The Spearman's correlation between two different methods was good (r=0.80). From exon arrays, we identified 586 genes that were down regulated and 363 gene were up regulated with aging (p<0.001). Most interestingly, overall expression of DNA methyl transferases Dnmt1, Dnmt3a, Dnmt3b were down regulated with aging. We also found that Dnmt3a2, the short isoform of Dnmt3a, which lacks the N-terminal region of Dnmt3a and represents the major isoform in ES cells, is more expressed in young HSC. For the RNA-seq analysis, we focused first on annotated transcripts derived from cloned mRNAs and we found 307 genes were down regulated and 1015 gene were up regulated with aging (p<0.05). Secondly, we sought to identify differentially expressed isoforms and also novel transcribed regions (antisense and novel genes). To characterize the genes showing differential regulation, we analyzed their functional associations and observed that the highest scoring annotation cluster was enriched in genes associated with translation, the immune network and hematopoietic cell lineage. We expect that the results of these experiments will reveal the global effect of DNA methylation on transcript stability and the translational state of target genes. Our findings will lend insight into the molecular mechanisms responsible for the pathologic changes associated with aging in HSCs. Disclosures: No relevant conflicts of interest to declare.

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Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass

Twin Research and Human Genetics ◽

10.1017/thg.2015.82 ◽

2015 ◽

Vol 18 (6) ◽

pp. 647-661 ◽

Cited By ~ 10

Author(s):

Aileen Bahl ◽

Eija Pöllänen ◽

Khadeeja Ismail ◽

Sarianna Sipilä ◽

Tuija M. Mikkola ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Body Composition ◽

Hormone Replacement Therapy ◽

Bone Mass ◽

Replacement Therapy ◽

Hormone Replacement ◽

Differentially Expressed ◽

Body Adiposity ◽

Genome Wide

The loss of estrogen during menopause causes changes in the female body, with wide-ranging effects on health. Estrogen-containing hormone replacement therapy (HRT) leads to a relief of typical menopausal symptoms, benefits bone and muscle health, and is associated with tissue-specific gene expression profiles. As gene expression is controlled by epigenetic factors (including DNA methylation), many of which are environmentally sensitive, it is plausible that at least part of the HRT-associated gene expression is due to changes in DNA methylation profile. We investigated genome-wide DNA methylation and gene expression patterns of white blood cells (WBCs) and their associations with body composition, including muscle and bone measures of monozygotic (MZ) female twin pairs discordant for HRT. We identified 7,855 nominally significant differentially methylated regions (DMRs) associated with 4,044 genes. Of the genes with DMRs, five (ACBA1, CCL5, FASLG, PPP2R2B, and UHRF1) were also differentially expressed. All have been previously associated with HRT or estrogenic regulation, but not with HRT-associated DNA methylation. All five genes were associated with bone mineral content (BMC), and ABCA1, FASLG, and UHRF1 were also associated with body adiposity. Our study is the first to show that HRT associates with genome-wide DNA methylation alterations in WBCs. Moreover, we show that five differentially expressed genes with DMRs associate with clinical measures, including body fat percentage, lean body mass, bone mass, and blood lipids. Our results indicate that at least part of the known beneficial HRT effects on body composition and bone mass may be regulated by DNA methylation associated alterations in gene expression in circulating WBCs.

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Bisphenol A-associated alterations in genome-wide DNA methylation and gene expression patterns reveal sequence-dependent and non-monotonic effects in human fetal liver

Environmental Epigenetics ◽

10.1093/eep/dvv006 ◽

2015 ◽

Vol 1 (1) ◽

pp. dvv006 ◽

Cited By ~ 33

Author(s):

Christopher Faulk ◽

Jung H. Kim ◽

Tamara R. Jones ◽

Richard C. McEachin ◽

Muna S. Nahar ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Bisphenol A ◽

Fetal Liver ◽

Expression Patterns ◽

Gene Expression Patterns ◽

Human Fetal Liver ◽

Sequence Dependent ◽

Genome Wide

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199 IN VITRO-DEVELOPED BOVINE BLASTOCYSTS ARE MARKED WITH ABERRANT HYPER- AND HYPO-METHYLATED GENOMIC REGIONS

Reproduction Fertility and Development ◽

10.1071/rdv27n1ab199 ◽

2015 ◽

Vol 27 (1) ◽

pp. 190

Author(s):

D. Salilew-Wondim ◽

M. Hoelker ◽

U. Besenfelder ◽

V. Havlicek ◽

F. Rings ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Expression Patterns ◽

Proximal Promoter ◽

Altered Gene Expression ◽

Genome Wide ◽

Altered Gene ◽

Genomic Regions

Most often, in vitro produced embryos display poor quality and altered gene expression patterns compared to their in vivo counterparts. Aberrant DNA methylation occurring during in vitro embryo development is believed to be one of the multifaceted factors which may cause altered gene expression and poor embryo quality. Here, we investigated the genome-wide DNA methylation patterns of in vitro derived embryos using the recently developed Bovine EmbryoGENE Methylation Platform (BEGMP) array (Shojaei Saadi et al. BMC Genomics 2014 15, 451. doi: 10.1186/1471-2164-15-451) to unravel the aberrantly methylated genomic region in in vitro developed embryos. For this, in vitro and in vivo produced blastocysts were produced and used for genome-wide DNA methylation analysis. In vitro blastocysts were produced from oocytes retrieved from ovaries collected from the local abattoir and matured, fertilized, and cultured in vitro using SOF media. The in vivo blastocysts were produced by superovulation and AI of Simmental heifers followed by uterine flushing. Genomic DNA (gDNA) was then isolated from four replicates (each 10 blastocysts) of in vivo and in vitro derived blastocysts using Allprep DNA/RNA micro kit (Qiagen, Valencia, CA, USA) and the gDNA was then fragmented using the MseI enzyme. Following this, MseLig21 and MseLig were ligated to the MseI-digested genomic fragments in the presence of Ligase enzyme. Methyl-sensitive enzymes, HpaII, AciI, and Hinp1I, were used to cleave unmethlayted genomic regions within the MseI-MseI region of the fragmented DNA. The gDNA was subjected to two rounds of ligation-mediated polymerase chain reaction (LM-PCR) amplification. After removal of the adapters, the amplified gDNA samples from in vivo or in vitro groups were labelled either Cy-3 or Cy-5 dyes in dye-swap design using ULS Fluorescent gDNA labelling kit (Kreatech Biotechnology BV, Amsterdam, The Netherlands). Hybridization was performed for 40 h at 65°C. Slides were scanned using Agilent's High-Resolution C Scanner (Agilent Technologies Inc., Santa Clara, CA, USA) and features were extracted with Agilent's Feature Extraction software (Agilent Technologies Inc.). The results have shown that from a total of 414 566 probes harboured by the BEGMP array, 248 453 and 253 147 probes were detected in in vitro and in vivo derived blastocysts, respectively. Data analysis using the linear modelling for microarray (LIMMA) package and R software (The R Project for Statistical Computing, Vienna, Austria) revealed a total of 3434 differentially methylated regions (DMRs; Fold change ≥1.5, P-value <0.05), of which 42 and 58% were hyper- and hypo-methylated, respectively, in in vitro derived blastocysts compared to their in vivo counterparts. The DMRs were found to be localised in the intronic, exonic, promoter, proximal promoter, and distal promoter, and some of the probes did not have nearby genes. In addition, 10.8% of the DMRs were found to be stretched in short, long, or intermediate CpG islands. Thus, this study demonstrated genome-wide dysregulation in the epigenome landscape of in vitro-derived embryos by the time they reach to the blastocysts stage.

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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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Gene network approach reveals co-expression patterns in nasal and bronchial epithelium

Scientific Reports ◽

10.1038/s41598-019-50963-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Kai Imkamp ◽

Victor Bernal ◽

Marco Grzegorzcyk ◽

Peter Horvatovich ◽

Cornelis J. Vermeulen ◽

...

Keyword(s):

Gene Expression ◽

Network Analysis ◽

Gene Expression Profiling ◽

Graphical Models ◽

Expression Profiling ◽

Expression Patterns ◽

Bronchial Epithelium ◽

Differentially Expressed ◽

Tobacco Exposure ◽

Genome Wide

Abstract Nasal gene expression profiling is a new approach to investigate the airway epithelium as a biomarker to study the activity and treatment responses of obstructive pulmonary diseases. We investigated to what extent gene expression profiling of nasal brushings is similar to that of bronchial brushings. We performed genome wide gene expression profiling on matched nasal and bronchial epithelial brushes from 77 respiratory healthy individuals. To investigate differences and similarities among regulatory modules, network analysis was performed on correlated, differentially expressed and smoking-related genes using Gaussian Graphical Models. Between nasal and bronchial brushes, 619 genes were correlated and 1692 genes were differentially expressed (false discovery rate <0.05, |Fold-change|>2). Network analysis of correlated genes showed pro-inflammatory pathways to be similar between the two locations. Focusing on smoking-related genes, cytochrome-P450 pathway related genes were found to be similar, supporting the concept of a detoxifying response to tobacco exposure throughout the airways. In contrast, cilia-related pathways were decreased in nasal compared to bronchial brushes when focusing on differentially expressed genes. Collectively, while there are substantial differences in gene expression between nasal and bronchial brushes, we also found similarities, especially in the response to the external factors such as smoking.

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