Abstract
Paratuberculosis in cattle causes substantial economic losses to the dairy industry. Exploring functional genes and corresponding regulatory pathways related to resistance or susceptibility to paratuberculosis is essential to the breeding of disease resistance in cattle. Co-analysis of genome-wide DNA methylation and transcriptome profiles is a critically important approach to understand potential regulatory mechanism underlying the development of diseases. In this study, we characterized the profiles of DNA methylation of jejunum from nine Holstein cows in clinical, subclinical, and healthy groups using whole-genome bisulfite sequencing (WGBS). The average methylation level in functional regions was 29.95% in the promoter, 29.65% in the 5’ untranslated region (UTR), 68.24% in exons, 71.55% in introns, and 72.81% in the 3’ UTR. A total of 3,911, 4,336, and 4,094 differentially methylated genes (DMGs) were detected in clinical vs. subclinical, clinical vs. healthy, and subclinical vs. healthy comparative group, respectively. Gene ontology (GO) and analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that these DMGs were significantly enriched in specific biological processes related to immune response, such as Th1 and Th2 cell differentiation, wnt, TNF, MAPK, ECM-receptor interaction, cellular senescence, calcium, and chemokine signaling pathways (q value <0.05). The integration of information about DMGs, differentially expressed genes (DEGs), and biological functions suggested nine genes CALCRL, TNC, GATA4, CD44, TGM3, CXCL9, CXCL10, PPARG, and NFATC1 as promising candidates related to resistance/susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP). This study reports on the high-resolution DNA methylation landscapes of the jejunum methylome across three conditions (clinical, subclinical, and healthy) in dairy cows. Our investigations integrated different sources of information about DMGs, DEGs, and pathways, enabling us to find nine functional genes that might have potential application in resisting paratuberculosis in dairy cattle.
Highlights
Animal health, as a main factor affecting the development of the animal husbandry economy, is being valued progressively more over time and incorporated into breeding programs
We found that the average methylation level was 15–20% in the transcription start site (TSS) and 65–75% in the gene body
The DNA methylation status of the promoter can affect gene expression via changes in chromatin structure or transcription efficiency (Miller and Grant, 2013). We found that both calcitonin receptor like receptor (CALCRL) and CXCL10 genes whose promoters contained two methylated sites showed lower expression levels based on our WGBS and RNA-seq data
Summary
As a main factor affecting the development of the animal husbandry economy, is being valued progressively more over time and incorporated into breeding programs. Paratuberculosis is referred to as Johne’s disease and has been reported all over the world bringing huge economic losses to the dairy industry, warranting more attention (Ott et al, 1999). The disease is a chronic debilitating enteritis caused by a Mycobacterium avium subspecies paratuberculosis (MAP) infection (Clarke, 1997), which has a long incubation period. Verschoor et al, 2010 reported that four single nucleotide polymorphisms (SNPs) in the IL10RA gene were significantly associated with paratuberculosis susceptibility in the Canadian Holstein cattle population (Verschoor et al, 2010). Studies have proved that jejunum is the main invasion and residence site of MAP, the infected jejunum wall is diffusely thickened, showing inflammation and tissue edema. We used jejunum tissue to explore the mechanism of paratuberculosis diseases in our study
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