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The Genomic Response To Corticosteroids In Airway Smooth Muscle
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A7184 - The Genomic Response To Corticosteroids In Airway Smooth Muscle
Author Block: W. Eckalbar1, S. Oh1, A. C. Mak1, M. White1, M. A. Seibold2, E. G. Burchard1, N. Ahituv3; 1Medicine, UCSF, San Francisco, CA, United States, 2Integrated Center for Genes, Enviroment and Health, National Jewish Health, Denver, CO, United States, 3Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, United States.
Asthma is the most common childhood disease and affects 8.4% of the population of the United States. Current guidelines recommend daily use of inhaled corticosteroids (ICS) for the management of asthma symptoms. In the US, ICS are the most commonly prescribed asthma medication. However, it has been estimated that as many as 40-60% of asthmatics are poor responders to treatment with ICS. While previous work has identified several genetic variants impacting ICS-response, progress has been limited by a lack of genomic data sets characterizing genes and gene regulatory elements responsive to ICS treatment in primary cell types. To address this, we have carried out RNA-seq and ChIP-seq with an antibody for H3K27ac, an active enhancer mark, in primary bronchial smooth muscle cells (BSMCs) treated with or without the corticosteroid, dexamethasone, at both early (4 H) and late (24 H and 48 H) time points. Through analysis of the RNA-seq data, we identified at total of 1,533 differentially expressed genes in response to dexamethasone. Genes differentially expressed in response to dexamethasone showed enrichment in Geno Ontology categories relating to cell proliferation, cytokine activity and cell migration. Through ChIP-seq analysis, we identified a total of 92,783 distinct peaks, 5,201 of which were differentially enriched with dexamethasone at least one time point. Across all ChIP-seq peaks, a total of 207 regions contained a SNP in high linkage (R2 ≥ 0.8) with asthma associated variants. Of these regions, 22 showed altered H3K27ac marks in response to dexamethasone. One of these peaks was 130kb away from the five-prime end of the gene Sprouty RTK Signaling Antagonist 2, SPRY2, a gene shown to be involved in the inhibition of cell proliferation. Ongoing work includes further characterization of this enhancer near SPRY2, including if asthma associated variants in this region lead to altered enhancer activity. By providing a comprehensive, genome-wide description of dexamethasone responsive genes and gene regulatory elements in primary BSMCs to the asthma community, we hope to aid the community in developing novel therapeutic approaches targeted at patients with poor asthma drug response.
Author Block: W. Eckalbar1, S. Oh1, A. C. Mak1, M. White1, M. A. Seibold2, E. G. Burchard1, N. Ahituv3; 1Medicine, UCSF, San Francisco, CA, United States, 2Integrated Center for Genes, Enviroment and Health, National Jewish Health, Denver, CO, United States, 3Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, United States.
Asthma is the most common childhood disease and affects 8.4% of the population of the United States. Current guidelines recommend daily use of inhaled corticosteroids (ICS) for the management of asthma symptoms. In the US, ICS are the most commonly prescribed asthma medication. However, it has been estimated that as many as 40-60% of asthmatics are poor responders to treatment with ICS. While previous work has identified several genetic variants impacting ICS-response, progress has been limited by a lack of genomic data sets characterizing genes and gene regulatory elements responsive to ICS treatment in primary cell types. To address this, we have carried out RNA-seq and ChIP-seq with an antibody for H3K27ac, an active enhancer mark, in primary bronchial smooth muscle cells (BSMCs) treated with or without the corticosteroid, dexamethasone, at both early (4 H) and late (24 H and 48 H) time points. Through analysis of the RNA-seq data, we identified at total of 1,533 differentially expressed genes in response to dexamethasone. Genes differentially expressed in response to dexamethasone showed enrichment in Geno Ontology categories relating to cell proliferation, cytokine activity and cell migration. Through ChIP-seq analysis, we identified a total of 92,783 distinct peaks, 5,201 of which were differentially enriched with dexamethasone at least one time point. Across all ChIP-seq peaks, a total of 207 regions contained a SNP in high linkage (R2 ≥ 0.8) with asthma associated variants. Of these regions, 22 showed altered H3K27ac marks in response to dexamethasone. One of these peaks was 130kb away from the five-prime end of the gene Sprouty RTK Signaling Antagonist 2, SPRY2, a gene shown to be involved in the inhibition of cell proliferation. Ongoing work includes further characterization of this enhancer near SPRY2, including if asthma associated variants in this region lead to altered enhancer activity. By providing a comprehensive, genome-wide description of dexamethasone responsive genes and gene regulatory elements in primary BSMCs to the asthma community, we hope to aid the community in developing novel therapeutic approaches targeted at patients with poor asthma drug response.
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