DNA Methylation Network Estimation with Sparse Latent Gaussian Graphical Model

AbstractInferring molecular interaction networks from genomics data is important for advancing our understanding of biological processes. Whereas considerable research effort has been placed on inferring such networks from gene expression data, network estimation from DNA methylation data has received very little attention due to the substantially higher dimensionality and complications with result interpretation for non-genic regions. To combat these challenges, we propose here an approach based on sparse latent Gaussian graphical model (SLGGM). The core idea is to perform network estimation on q latent variables as opposed to d CpG sites, with q<<d. To impose a correspondence between the latent variables and genes, we use the distance between CpG sites and transcription starting sites of the genes to generate a prior on the CpG sites’ latent class membership. We evaluate this approach on synthetic data, and show on real data that the gene network estimated from DNA methylation data significantly explains gene expression patterns in unseen datasets.

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Abstract P098: An Epigenome-wide Study of Obesity in African American Youth and Young Adults: Novel Findings, Replication in Neutrophils and Relationship With Gene Expression

Circulation ◽

10.1161/circ.135.suppl_1.p098 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Xiaoling Wang ◽

Yue Pan ◽

Haidong Zhu ◽

Guang Hao ◽

Xin Wang ◽

...

Keyword(s):

Gene Expression ◽

Older Adults ◽

Dna Methylation ◽

Young Adults ◽

Methylation Data ◽

Middle Aged ◽

Cpg Sites ◽

Genome Wide ◽

Obesity Status ◽

Youth And Young Adults

Background: Several large-scale epigenome wide association studies on obesity-related DNA methylation changes have been published and in total identified 46 CpG sites. These studies were conducted in middle-aged and older adults of Caucasians and African Americans (AAs) using leukocytes. To what extend these signals are independent of cell compositions as well as to what extend they may influence gene expression have not been systematically investigated. Furthermore, the high prevalence of obesity comorbidities in middle-aged or older population may hide or bias obesity itself related DNA methylation changes. Methods: In this study of healthy AA youth and young adults, genome wide DNA methylation data from leukocytes were obtained from three independent studies: EpiGO study (96 obese cases vs. 92 lean controls, aged 14-21, 50% females, test of interest is obesity status), LACHY study (284 participants from general population, aged 14-18, 50% females, test of interest is BMI), and Georgia Stress and Heart study (298 participants from general population, aged 18-38, 52% females, test of interest is BMI) using the Infinium HumanMethylation450 BeadChip. Genome wide DNA methylation data from purified neutrophils as well as genome wide gene expression data from leukocytes using Illumina HT12 V4 array were also obtained for the EpiGO samples. Results: The meta-analysis on the 3 cohorts identified 76 obesity related CpG sites in leukocytes with p<1х10 -7 . Out of the 46 previously identified CpG sites, 36 can be replicated in this AA youth and young adult sample with same direction and p<0.05. Out of the 107 CpG sites including the 36 replicated ones and the 71 newly identified ones, 71 CpG sites (66%) had their relationship with obesity replicated in purified neutrophils (p<0.05). The analysis on the cis regulation of the 107 CpG sites on gene expression showed that 59 CpG sites had at least one gene within 250kb having expression difference between obese cases and lean controls. Furthermore, out of the 59 CpG sites, 6 showed significantly negative correlations and 1 showed significantly positive correlation with the differentially expressed genes. These CpG sites located in SOCS3, CISH, ABCG1, PIM3 and PTGDS genes. Conclusion: In this study of AA youth and young adults, we identified novel CpG sites associated with obesity and replicated majority of the CpG sites previously identified in middle-aged and older adults. For the first time, we showed that majority of the obesity related CpG sites identified from leukocytes are not driven by cell compositions and provided the direct link between DNA methylation-gene expression-obesity status for 7 CpG sites in 5 genes.

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The Expression Level of mRNA, Protein, and DNA Methylation Status of FOSL2 of Uyghur in XinJiang in Type 2 Diabetes

Journal of Diabetes Research ◽

10.1155/2016/5957404 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Jun Li ◽

Siyuan Li ◽

Ying Hu ◽

Guolei Cao ◽

Siyao Wang ◽

...

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Dna Methylation ◽

Methylation Status ◽

Methylation Data ◽

Biochemical Indicators ◽

Expression Levels ◽

Protein Levels ◽

Cpg Sites

Objective. We investigated the expression levels of both FOSL2 mRNA and protein as well as evaluating DNA methylation in the blood of type 2 diabetes mellitus (T2DM) Uyghur patients from Xinjiang. This study also evaluated whether FOSL2 gene expression had demonstrated any associations with clinical and biochemical indicators of T2DM. Methods. One hundred Uyghur subjects where divided into two groups, T2DM and nonimpaired glucose tolerance (NGT) groups. DNA methylation of FOSL2 was also analyzed by MassARRAY Spectrometry and methylation data of individual units were generated by the EpiTyper v1.0.5 software. The expression levels of FOS-like antigen 2 (FOSL2) and the protein expression levels were analyzed. Results. Significant differences were observed in mRNA and protein levels when compared with the NGT group, while methylation rates of eight CpG units within the FOSL2 gene were higher in the T2DM group. Methylation of CpG sites was found to inversely correlate with expression of other markers. Conclusions. Results show that a correlation between mRNA, protein, and DNA methylation of FOSL2 gene exists among T2DM patients from Uyghur. FOSL2 protein and mRNA were downregulated and the DNA became hypermethylated, all of which may be involved in T2DM pathogenesis in this population.

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Somatic cytochrome c (CYCS) gene expression and promoter-specific DNA methylation in a porcine model of prenatal exposure to maternal dietary protein excess and restriction

British Journal Of Nutrition ◽

10.1017/s0007114511003667 ◽

2011 ◽

Vol 107 (6) ◽

pp. 791-799 ◽

Cited By ~ 13

Author(s):

Simone Altmann ◽

Eduard Murani ◽

Manfred Schwerin ◽

Cornelia C. Metges ◽

Klaus Wimmers ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Porcine Model ◽

Expression Patterns ◽

Methylation Status ◽

Special Focus ◽

Cpg Sites ◽

Low Protein ◽

Protein Supply ◽

The Impact

There is growing evidence that maternal nutrition during gestation has an important effect on offspring development as well as on their gene expression with long-term effects on the metabolic state. A potential mechanism forming long-lasting gene expression patterns is DNA methylation of cytosine in CpG dinucleotides within the promoter region of distinct genes. There has been special focus on mitochondrial dysfunction by prenatal malnourishment over the recent years. To this end, we investigated the gene expression of somatic cytochrome c (CYCS), an important member of the respiratory chain, in a porcine model of gestational protein over- and undersupply at 94 d post-conception and 1, 28 and 188 d of age, and analysed the association with the DNA methylation status within the CYCS promoter. Gene expression on day 1 post natum showed a significant increase in the low protein (LP) group (P = 0·0005) and a slight increase in the high protein (HP) group (P = 0·079) compared with the control (CO) group in the liver. The mean of the methylation level over forty-seven CpG sites from nucleotide (nt) − 417 to − 10 was significantly decreased in the LP (P = 0·007) and HP (P = 0·009) groups compared with that in the CO group. Excess and restricted protein supply during pregnancy led to hypomethylation of a number of CpG sites in the CYCS promoter, including those representing putative transcription factor-binding sites, associated with elevated expression levels. However, the impact of the low-protein gestation diet is more pronounced, indicating that the offspring could better adapt to excess rather than restricted protein supply.

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Age-related differences in monocyte DNA methylation and immune function in healthy Kenyan adults and children

Immunity & Ageing ◽

10.1186/s12979-021-00223-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Katherine R. Dobbs ◽

Paula Embury ◽

Emmily Koech ◽

Sidney Ogolla ◽

Stephen Munga ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Young Adults ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Innate Immune ◽

Inflammatory Gene Expression ◽

Cpg Sites ◽

Age Related ◽

Adults And Children

Abstract Background Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profiles in monocytes from young adults and children from western Kenya. Results We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles. Conclusions These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

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Gene expression profiling of epigenetic chromatin modification enzymes and histone marks by cigarette smoke: implications for COPD and lung cancer

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00253.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. L1245-L1258 ◽

Cited By ~ 19

Author(s):

Isaac K. Sundar ◽

Irfan Rahman

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Dna Methylation ◽

Cigarette Smoke ◽

Histone Modifications ◽

Expression Patterns ◽

Chromatin Modification ◽

Gene Expression Patterns ◽

Validation Data ◽

Histone Marks

Chromatin-modifying enzymes mediate DNA methylation and histone modifications on recruitment to specific target gene loci in response to various stimuli. The key enzymes that regulate chromatin accessibility for maintenance of modifications in DNA and histones, and for modulation of gene expression patterns in response to cigarette smoke (CS), are not known. We hypothesize that CS exposure alters the gene expression patterns of chromatin-modifying enzymes, which then affects multiple downstream pathways involved in the response to CS. We have, therefore, analyzed chromatin-modifying enzyme profiles and validated by quantitative real-time PCR (qPCR). We also performed immunoblot analysis of targeted histone marks in C57BL/6J mice exposed to acute and subchronic CS, and of lungs from nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). We found a significant increase in expression of several chromatin modification enzymes, including DNA methyltransferases, histone acetyltransferases, histone methyltransferases, and SET domain proteins, histone kinases, and ubiquitinases. Our qPCR validation data revealed a significant downregulation of Dnmt1, Dnmt3a, Dnmt3b, Hdac2, Hdac4, Hat1, Prmt1, and Aurkb. We identified targeted chromatin histone marks (H3K56ac and H4K12ac), which are induced by CS. Thus CS-induced genotoxic stress differentially affects the expression of epigenetic modulators that regulate transcription of target genes via DNA methylation and site-specific histone modifications. This may have implications in devising epigenetic-based therapies for COPD and lung cancer.

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DNA Methylation Landscape of 16 Canine Somatic Tissues by Methylation-Sensitive Restriction Enzyme-Based Next Generation Sequencing

10.21203/rs.3.rs-146319/v1 ◽

2021 ◽

Author(s):

Jumpei Yamazaki ◽

Yuki Matsumoto ◽

Jaroslav Jelinek ◽

Teita Ishizaki ◽

Shingo Maeda ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Next Generation Sequencing ◽

Restriction Enzyme ◽

Companion Animals ◽

Next Generation ◽

Cpg Sites ◽

Somatic Tissues ◽

Methylation Sensitive Restriction Enzyme ◽

Generation Sequencing

Abstract Background: DNA methylation plays important functions in gene expression regulation that is involved in individual development and various diseases. DNA methylation has been well studied in human and model organisms, but only limited data exist in companion animals like dog. Results: Using methylation-sensitive restriction enzyme-based next generation sequencing (Canine DREAM), we obtained canine DNA methylation maps from 16 somatic tissues. In total, we evaluated 130,861 CpG sites. The majority of CpG sites were either highly methylated (>70%, 52.5%-64.6% of all CpG sites analyzed) or unmethylated (<30%, 22.5%-28.0% of all CpG sites analyzed) which are methylation patterns similar to other species. The overall methylation status of CpG sites across the 32 methylomes were remarkably similar. However, the tissue types were clearly defined by principle component analysis and hierarchical clustering analysis with DNA methylome. We found 6416 CpG sites located closely at promoter region of genes and inverse correlation between DNA methylation and gene expression of these genes. Conclusions: Our study provides basic dataset for DNA methylation profiles in dogs.

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An integrative multi-omics approach in Sjögren’s Syndrome identifies novel genetic drivers with regulatory function and disease-specificity

10.1101/2020.09.14.20192211 ◽

2020 ◽

Author(s):

María Teruel ◽

Guillermo Barturen ◽

Manuel Martínez-Bueno ◽

Miguel Barroso ◽

Olivia Castelli ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Sjögren’S Syndrome ◽

Genetic Variants ◽

Sjögren's Syndrome ◽

Expression Patterns ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Regulatory Function ◽

Sjögren‘S Syndrome

ABSTRACTPrimary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overexpression effects, that also exhibit increased variability, in many already known IFN-regulated genes. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of novel genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified new genetic variants associated with SS that mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, DNA methylation, gene expression and SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

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Maternal and Post-weaning High-Fat Diets Produce Distinct DNA Methylation Patterns in Hepatic Metabolic Pathways within Specific Genomic Contexts

International Journal of Molecular Sciences ◽

10.3390/ijms20133229 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3229 ◽

Cited By ~ 4

Author(s):

Moody ◽

Wang ◽

Jung ◽

Chen ◽

Pan

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Metabolic Pathways ◽

Expression Patterns ◽

Sprague Dawley ◽

High Fat ◽

Differentially Methylated Genes ◽

High Fat Diets ◽

Diet Intake ◽

Fat Diets

Calorie-dense high-fat diets (HF) are associated with detrimental health outcomes, including obesity, cardiovascular disease, and diabetes. Both pre- and post-natal HF diets have been hypothesized to negatively impact long-term metabolic health via epigenetic mechanisms. To understand how the timing of HF diet intake impacts DNA methylation and metabolism, male Sprague–Dawley rats were exposed to either maternal HF (MHF) or post-weaning HF diet (PHF). At post-natal week 12, PHF rats had similar body weights but greater hepatic lipid accumulation compared to the MHF rats. Genome-wide DNA methylation was evaluated, and analysis revealed 1744 differentially methylation regions (DMRs) between the groups with the majority of the DMR located outside of gene-coding regions. Within differentially methylated genes (DMGs), intragenic DNA methylation closer to the transcription start site was associated with lower gene expression, whereas DNA methylation further downstream was positively correlated with gene expression. The insulin and phosphatidylinositol (PI) signaling pathways were enriched with 25 DMRs that were associated with 20 DMGs, including PI3 kinase (Pi3k), pyruvate kinase (Pklr), and phosphodiesterase 3 (Pde3). Together, these results suggest that the timing of HF diet intake determines DNA methylation and gene expression patterns in hepatic metabolic pathways that target specific genomic contexts.

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Changes in DNA Methylation and Gene Expression of Insulin and Obesity-Related Gene PIK3R1 after Roux-en-Y Gastric Bypass

International Journal of Molecular Sciences ◽

10.3390/ijms21124476 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4476

Author(s):

Marcela A S Pinhel ◽

Natália Y Noronha ◽

Carolina F Nicoletti ◽

Vanessa AB Pereira ◽

Bruno AP de Oliveira ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Weight Loss ◽

Gastric Bypass ◽

Related Gene ◽

Cpg Sites ◽

Genome Wide ◽

Genetically Determined ◽

Methylation Patterns ◽

Weight Loss Interventions

Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how the gene expression and DNA methylation of PIK3R1, an obesity and insulin-related gene, change after RYGB. Blood samples were obtained from 13 women (35.9 ± 9.2 years) with severe obesity before and six months after surgical procedure. Whole blood transcriptome and epigenomic patterns were assessed by microarray-based, genome-wide technologies. A total of 1966 differentially expressed genes were identified in the pre- and postoperative periods of RYGB. From these, we observed that genes involved in obesity and insulin pathways were upregulated after surgery. Then, the PIK3R1 gene was selected for further RT-qPCR analysis and cytosine-guanine nucleotide (CpG) sites methylation evaluation. We observed that the PI3KR1 gene was upregulated, and six DNA methylation CpG sites were differently methylated after bariatric surgery. In conclusion, we found that RYGB upregulates genes involved in obesity and insulin pathways.

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Testing cell-type-specific mediation effects in genome-wide epigenetic studies

Briefings in Bioinformatics ◽

10.1093/bib/bbaa131 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xiangyu Luo ◽

Joel Schwartz ◽

Andrea Baccarelli ◽

Zhonghua Liu

Keyword(s):

Dna Methylation ◽

Mediation Analysis ◽

Methylation Data ◽

Cell Type ◽

Multiple Testing Procedure ◽

Mediation Effects ◽

Cpg Sites ◽

Genome Wide ◽

A Cell ◽

Cell Type Specific

Abstract Epigenome-wide mediation analysis aims to identify DNA methylation CpG sites that mediate the causal effects of genetic/environmental exposures on health outcomes. However, DNA methylations in the peripheral blood tissues are usually measured at the bulk level based on a heterogeneous population of white blood cells. Using the bulk level DNA methylation data in mediation analysis might cause confounding bias and reduce study power. Therefore, it is crucial to get fine-grained results by detecting mediation CpG sites in a cell-type-specific way. However, there is a lack of methods and software to achieve this goal. We propose a novel method (Mediation In a Cell-type-Specific fashion, MICS) to identify cell-type-specific mediation effects in genome-wide epigenetic studies using only the bulk-level DNA methylation data. MICS follows the standard mediation analysis paradigm and consists of three key steps. In step1, we assess the exposure-mediator association for each cell type; in step 2, we assess the mediator-outcome association for each cell type; in step 3, we combine the cell-type-specific exposure-mediator and mediator-outcome associations using a multiple testing procedure named MultiMed [Sampson JN, Boca SM, Moore SC, et al. FWER and FDR control when testing multiple mediators. Bioinformatics 2018;34:2418–24] to identify significant CpGs with cell-type-specific mediation effects. We conduct simulation studies to demonstrate that our method has correct FDR control. We also apply the MICS procedure to the Normative Aging Study and identify nine DNA methylation CpG sites in the lymphocytes that might mediate the effect of cigarette smoking on the lung function.

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