Abstract
DNA methylation changes play essential roles in regulating the activities of genes involved in immune responses. Understanding of variable DNA methylation linked to immune responses may contribute to identifying biologically promising epigenetic markers for pathogenesis of diseases. Here, we generated genome-wide DNA methylation and transcriptomic profiles of six pairs of polyinosinic-polycytidylic acid-treated pig peripheral blood mononuclear cell (PBMC) samples and corresponding controls using methylated DNA immunoprecipitation sequencing and RNA sequencing. Comparative methylome analyses identified 5,827 differentially methylated regions and 615 genes showing differential expression between the two groups. Integrative analyses revealed inverse associations between DNA methylation around transcriptional start site and gene expression levels. Furthermore, 70 differentially methylated and expressed genes were identified such as TNFRSF9, IDO1 and EBI3. Functional annotation revealed the enriched categories including positive regulation of immune system process and regulation of leukocyte activation. These findings demonstrated DNA methylation changes occurring in immune responses of PBMCs to poly I:C stimulation and a subset of genes potentially regulated by DNA methylation in the immune responses. The PBMC DNA methylome provides an epigenetic overview of this physiological system in response to viral infection, and we expect it to constitute a valuable resource for future epigenetic epidemiology studies in pigs.
Highlights
Epigenetic alterations are a regular and natural occurrence that can result in heritable changes in gene expression without changing the underlying DNA sequence while being influenced by genetic changes and environmental cues[1]
Through a genome-wide comparative methylome analysis of pig peripheral blood mononuclear cell (PBMC), we revealed the associations of epigenetic alterations with the responses of PBMCs to immune stimulation by the viral pathogen
Further integrated analysis of MeDIP-seq and RNA-seq data allowed the identification of immune response-related genes that may be driven by DNA methylation
Summary
Epigenetic alterations are a regular and natural occurrence that can result in heritable changes in gene expression without changing the underlying DNA sequence while being influenced by genetic changes and environmental cues[1]. The TLR3 agonist polyinosinic-polycytidylic acid (poly I:C), an artificial surrogate for double-stranded RNA (dsRNA) virus, has been extensively used to simulate viral infection[16] As such kind of external pathogenic stimuli can conduce to epigenetic changes, understanding of the variable DNA methylation linked to immune and inflammatory responses of PBMCs may contribute to identifying biologically promising epigenetic markers for pathogenesis of viral diseases. In this study, using the pig as a model we established an in vitro model system to analyze changes in methylome profiling of PBMCs in response to poly I:C stimulation and explore potential roles of DNA methylation in this process. The comprehensive analysis of PBMC methylome will advance our understanding of epigenetic contributions to immune responses to viral infection, and aid in the identification of potential epigenetic biomarkers associated with responsiveness to viruses
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