SwePub - search: WFRF:(Merid Simon Kebede)

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1.	Eriksson Ström, Jonas, et al. (author) Chronic obstructive pulmonary disease is associated with epigenome-wide differential methylation in BAL lung cells 2022 In: American Journal of Respiratory Cell and Molecular Biology. - : American Thoracic Society. - 1044-1549 .- 1535-4989. ; 66:6, s. 638-647 Journal article (peer-reviewed)abstract DNA methylation patterns in chronic pulmonary obstructive disease (COPD) might offer new insights into disease pathogenesis. To assess methylation profiles in the main COPD target organ, we performed an epigenome-wide association study on BAL cells. Bronchoscopies were performed in 18 subjects with COPD and 15 control subjects (ex- and current smokers). DNA methylation was measured using the Illumina MethylationEPIC BeadChip Kit, covering more than 850,000 CpGs. Differentially methylated positions (DMPs) were examined for 1) enrichment in pathways and functional gene relationships using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology, 2) accelerated aging using Horvath's epigenetic clock, 3) correlation with gene expression, and 4) colocalization with genetic variation. We found 1,155 Bonferroni-significant (P < 6.74 × 10-8) DMPs associated with COPD, many with large effect sizes. Functional analysis identified biologically plausible pathways and gene relationships, including enrichment for transcription factor activity. Strong correlation was found between DNA methylation and chronological age but not between COPD and accelerated aging. For 79 unique DMPs, DNA methylation correlated significantly with gene expression in BAL cells. Thirty-nine percent of DMPs were colocalized with COPD-associated SNPs. To the best of our knowledge, this is the first epigenome-wide association study of COPD on BAL cells, and our analyses revealed many differential methylation sites. Integration with mRNA data showed a strong functional readout for relevant genes, identifying sites where DNA methylation might directly affect expression. Almost half of DMPs were colocated with SNPs identified in previous genome-wide association studies of COPD, suggesting joint genetic and epigenetic pathways related to disease.
2.	Merid, Simon Kebede (author) Molecular signatures of early life exposures and complex diseases : applications using epigenetics and transcriptomics data 2022 Doctoral thesis (other academic/artistic)abstract Environmental exposures and early life stressors may influence developmental processes and have long-term health consequences, potentially mediated by molecular mechanisms such as epigenetic modifications. The most extensively studied epigenetic mechanism is DNA methylation, which has been proposed to constitute a link between genetic and environmental factors. Epigenetic patterns established early in life (already in utero) may affect how a gene is expressed throughout life, and thereby increase susceptibility to chronic disease. Other factors like genetics and repeated airway infections also influence disease risk. Chronic obstructive pulmonary disease (COPD) is a complex disease considered a major global health problem, with tobacco smoking being one of the main risk factors. The role that deoxyribonucleic acid (DNA) methylation might play in the pathogenesis of COPD has not been comprehensively studied. Bronchoalveolar lavage (BAL) cells from the airways and alveolar space are considered key targets for COPD. Peanut allergy is another complex disease – one of the most common food allergies and the leading cause of anaphylaxis among children. Peanut oral immunotherapy (pOIT) can lead to desensitization and tolerance, and combined treatment with anti-immunoglobulin E (IgE) using omalizumab may facilitate oral immunotherapy initiation. The mechanisms of oral immunotherapy-induced tolerance, including possible changes at the transcriptional level, are not well understood. The main aim of this thesis was to identify molecular signatures of early-life exposures, chronic respiratory disease, as well as allergy treatment responses. In Study I, the association between gestational age and DNA methylation patterns (at 5´-cytosine-phosphate-guanine-3´ sites, CpGs, across the genome) was investigated in newborns and older children from the large The Pregnancy And Childhood Epigenetics (PACE) consortium meta-analysis, including 11,000 participants in 26 independent cohorts. Changes in DNA methylation associated with gestational age were explored in additional pediatric cohorts at 4–18 years. The functional follow-up and correlation analyses between DNA methylation and gene expression were performed using cord blood. In addition, we evaluated DNA methylation profiles in other relevant tissues (fetal brain and lung) related to gestational age. We found numerous epigenome-wide differentially methylated CpGs related to gestational age at birth. Notably, many of the identified CpGs had not previously been associated with gestational age. Several CpGs affected the expression of nearby genes, displayed a strong functional link with human diseases, and were enriched in biological processes essential for fetal development. The epigenetic plasticity of fetal development across tissues was captured by many methylation sites. However, the majority of methylation levels underwent changes over time and stabilized after school age. In Study II, the impact of outdoor exposure to particles of less than 2.5 micrometers in size (PM2.5) at birth and current residential address on gene expression was explored in childhood and adolescence in the MeDALL consortium encompassing three European birth cohorts. In addition, the functional molecular patterns of PM2.5 exposure were evaluated by integrating protein-protein interaction and genome-wide gene expression with matched DNA methylation. We found evidence suggestive of gene signatures in children and adolescents associated with PM2.5 exposure at birth. However, the integration of multi-omics profiles revealed several epigenetic deregulation gene module interactome hotspots where both methylation and expression levels were affected by PM2.5 exposure at birth and current address. Some of the identified genes were associated with diseases known to be caused by or worsened by air pollution exposure. In Study III, the pivotal role of DNA methylation profiles in BAL cells primarily macrophages was assessed in relation to COPD status and smoking in adults, to gain a further understanding of the disease pathogenesis. Several CpGs were associated with COPD in BAL cells, across the epigenome. Many of the identified CpGs displayed a strong functional link with gene expression and pathways enriched in cancer, various types of cell junctions, and cyclic adenosine monophosphate (cAMP) and Rap1 signaling. Notably, almost half of the CpGs co-located in the proximity of COPD-associated single nucleotide polymorphisms, which suggests that both genetic and epigenetic mechanisms are of importance at certain loci. In Study IV, the blood gene expression profiles before, during, and after pOIT and Omalizumab (O, an anti-IgE monoclonal antibody) treatment were evaluated in adolescent patients with severe peanut allergy using high-throughput ribonucleic acid (RNA) sequencing. At the first two timepoints, baseline and pOIT start, we investigated if there was an effect of omalizumab treatment on gene expression. In addition, a longitudinal analysis was performed to evaluate the combined effect of pOIT with Omalizumab (pOIT+O). We also evaluated the overlap of pOIT+O-associated genes with genes associated with acute peanut allergic reactions in a previously published clinical study by Watson et al1. First, we showed that the blood gene expression of patients with peanut allergy was not altered by omalizumab treatment alone. However, the combined effect of pOIT+O showed up- and downregulation of several genes involved in T-cell functions and immune responses. Furthermore, comparing our findings with genes previously found to be affected during acute peanut allergic reactions suggested that pOIT+O may play a role in altering the same genes (in the opposite direction). In conclusion, we demonstrated that DNA methylation profiles are related to gestational age at birth. The identified methylation sites were linked to human diseases and are likely to be involved in biological processes essential for fetal development. Most of the methylation sites also affect expression of nearby genes and reflect epigenetic plasticity of fetal development across tissues. We highlighted the added value of multi-omics analyses in relation to information on PM2.5 exposure that may enhance the understanding of molecular mechanisms and biological responses induced by air pollutants. Moreover, we revealed COPD-associated methylation changes in macrophage-dense BAL cells with a strong functional link to different pathways and gene expression. Both genetic and epigenetic mechanisms play important roles at certain loci. We also provided insights into the transcriptome profiles during pOIT and combined treatment with omalizumab.

Merid, Simon Kebede (author)
Molecular signatures of early life exposures and complex diseases : applications using epigenetics and transcriptomics data
2022
Doctoral thesis (other academic/artistic)abstract
- Environmental exposures and early life stressors may influence developmental processes and have long-term health consequences, potentially mediated by molecular mechanisms such as epigenetic modifications. The most extensively studied epigenetic mechanism is DNA methylation, which has been proposed to constitute a link between genetic and environmental factors. Epigenetic patterns established early in life (already in utero) may affect how a gene is expressed throughout life, and thereby increase susceptibility to chronic disease. Other factors like genetics and repeated airway infections also influence disease risk. Chronic obstructive pulmonary disease (COPD) is a complex disease considered a major global health problem, with tobacco smoking being one of the main risk factors. The role that deoxyribonucleic acid (DNA) methylation might play in the pathogenesis of COPD has not been comprehensively studied. Bronchoalveolar lavage (BAL) cells from the airways and alveolar space are considered key targets for COPD. Peanut allergy is another complex disease – one of the most common food allergies and the leading cause of anaphylaxis among children. Peanut oral immunotherapy (pOIT) can lead to desensitization and tolerance, and combined treatment with anti-immunoglobulin E (IgE) using omalizumab may facilitate oral immunotherapy initiation. The mechanisms of oral immunotherapy-induced tolerance, including possible changes at the transcriptional level, are not well understood. The main aim of this thesis was to identify molecular signatures of early-life exposures, chronic respiratory disease, as well as allergy treatment responses. In Study I, the association between gestational age and DNA methylation patterns (at 5´-cytosine-phosphate-guanine-3´ sites, CpGs, across the genome) was investigated in newborns and older children from the large The Pregnancy And Childhood Epigenetics (PACE) consortium meta-analysis, including 11,000 participants in 26 independent cohorts. Changes in DNA methylation associated with gestational age were explored in additional pediatric cohorts at 4–18 years. The functional follow-up and correlation analyses between DNA methylation and gene expression were performed using cord blood. In addition, we evaluated DNA methylation profiles in other relevant tissues (fetal brain and lung) related to gestational age. We found numerous epigenome-wide differentially methylated CpGs related to gestational age at birth. Notably, many of the identified CpGs had not previously been associated with gestational age. Several CpGs affected the expression of nearby genes, displayed a strong functional link with human diseases, and were enriched in biological processes essential for fetal development. The epigenetic plasticity of fetal development across tissues was captured by many methylation sites. However, the majority of methylation levels underwent changes over time and stabilized after school age. In Study II, the impact of outdoor exposure to particles of less than 2.5 micrometers in size (PM2.5) at birth and current residential address on gene expression was explored in childhood and adolescence in the MeDALL consortium encompassing three European birth cohorts. In addition, the functional molecular patterns of PM2.5 exposure were evaluated by integrating protein-protein interaction and genome-wide gene expression with matched DNA methylation. We found evidence suggestive of gene signatures in children and adolescents associated with PM2.5 exposure at birth. However, the integration of multi-omics profiles revealed several epigenetic deregulation gene module interactome hotspots where both methylation and expression levels were affected by PM2.5 exposure at birth and current address. Some of the identified genes were associated with diseases known to be caused by or worsened by air pollution exposure. In Study III, the pivotal role of DNA methylation profiles in BAL cells primarily macrophages was assessed in relation to COPD status and smoking in adults, to gain a further understanding of the disease pathogenesis. Several CpGs were associated with COPD in BAL cells, across the epigenome. Many of the identified CpGs displayed a strong functional link with gene expression and pathways enriched in cancer, various types of cell junctions, and cyclic adenosine monophosphate (cAMP) and Rap1 signaling. Notably, almost half of the CpGs co-located in the proximity of COPD-associated single nucleotide polymorphisms, which suggests that both genetic and epigenetic mechanisms are of importance at certain loci. In Study IV, the blood gene expression profiles before, during, and after pOIT and Omalizumab (O, an anti-IgE monoclonal antibody) treatment were evaluated in adolescent patients with severe peanut allergy using high-throughput ribonucleic acid (RNA) sequencing. At the first two timepoints, baseline and pOIT start, we investigated if there was an effect of omalizumab treatment on gene expression. In addition, a longitudinal analysis was performed to evaluate the combined effect of pOIT with Omalizumab (pOIT+O). We also evaluated the overlap of pOIT+O-associated genes with genes associated with acute peanut allergic reactions in a previously published clinical study by Watson et al1. First, we showed that the blood gene expression of patients with peanut allergy was not altered by omalizumab treatment alone. However, the combined effect of pOIT+O showed up- and downregulation of several genes involved in T-cell functions and immune responses. Furthermore, comparing our findings with genes previously found to be affected during acute peanut allergic reactions suggested that pOIT+O may play a role in altering the same genes (in the opposite direction). In conclusion, we demonstrated that DNA methylation profiles are related to gestational age at birth. The identified methylation sites were linked to human diseases and are likely to be involved in biological processes essential for fetal development. Most of the methylation sites also affect expression of nearby genes and reflect epigenetic plasticity of fetal development across tissues. We highlighted the added value of multi-omics analyses in relation to information on PM2.5 exposure that may enhance the understanding of molecular mechanisms and biological responses induced by air pollutants. Moreover, we revealed COPD-associated methylation changes in macrophage-dense BAL cells with a strong functional link to different pathways and gene expression. Both genetic and epigenetic mechanisms play important roles at certain loci. We also provided insights into the transcriptome profiles during pOIT and combined treatment with omalizumab.

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