Functional annotation of the cattle genome through systematic discovery and characterization of chromatin states and butyrate-induced variations

Abstract

Background The functional annotation of genomes, including chromatin accessibility and modifications, is important for understanding and effectively utilizing the increased amount of genome sequences reported. However, while such annotation has been well explored in a diverse set of tissues and cell types in human and model organisms, relatively little data are available for livestock genomes, hindering our understanding of complex trait variation, domestication, and adaptive evolution. Here, we present the first complete global landscape of regulatory elements in cattle and explore the dynamics of chromatin states in rumen epithelial cells induced by the rumen developmental regulator—butyrate. Results We established the first global map of regulatory elements (15 chromatin states) and defined their coordinated activities in cattle, through genome-wide profiling for six histone modifications, RNA polymerase II, CTCF-binding sites, DNA accessibility, DNA methylation, and transcriptome in rumen epithelial primary cells (REPC), rumen tissues, and Madin-Darby bovine kidney epithelial cells (MDBK). We demonstrated that each chromatin state exhibited specific enrichment for sequence ontology, transcription, methylation, trait-associated variants, gene expression-associated variants, selection signatures, and evolutionarily conserved elements, implying distinct biological functions. After butyrate treatments, we observed that the weak enhancers and flanking active transcriptional start sites (TSS) were the most dynamic chromatin states, occurred concomitantly with significant alterations in gene expression and DNA methylation, which was significantly associated with heifer conception rate and stature economic traits. Conclusion Our results demonstrate the crucial role of functional genome annotation for understanding genome regulation, complex trait variation, and adaptive evolution in livestock. Using butyrate to induce the dynamics of the epigenomic landscape, we were able to establish the correlation among nutritional elements, chromatin states, gene activities, and phenotypic outcomes. Electronic supplementary material The online version of this article (10.1186/s12915-019-0687-8) contains supplementary material, which is available to authorized users.

Epigenomics and genotype-phenotype association analyses reveal conserved genetic architecture of complex traits in cattle and human

“…In this study, we confirmed this in cattle by observing a higher enrichment of GWAS hits and selection signals in tissue-specific promoters (i.e., H3K4me3 and H3k27ac) than in tissue-specific gene body regions (i.e., H3K36me3). This was in agreement with our recent study that found GWAS signals and selection signature were significantly enriched in chromatin states relevant with active promoters and enhancers in cattle [16]. A previous study on sheep also reported that cis-regulatory elements contributed to the adaptive evolution of modern breeds by mapping selection signatures to chromatin states that were cross-species mapped from human [66].…”

“…The Functional Annotation of Animal Genomes consortium (FAANG), still in its early phase, aims to generate a comprehensive catalogue of regulatory elements for domestic and non-model organism species [15]. By constructing the first map of regulatory elements in the livestock species, we recently showed that GWAS signals of multiple complex traits were significantly enriched in active promoters and enhancers in bovine rumen epithelial primary cells [16].…”

Analyses of inter-individual variations of sperm DNA methylation and their potential implications in cattle

“…2d). Based on the 15 chromatin states in bovine rumen cells predicted using histone modifications (H3K4me3, H3K4me1, H3K27ac, H3K27me3) and other epigenome information (ATAC-seq and CTCF binding sites) [25], we observed MHBs had a significant enrichment for flanking bivalent TSS/enhancer (enrichment factor: 17) and active TSS i.e. promoters (enrichment factor: 11) (Fig.…”

“…d Enrichment of MHBs in known genomic features. e Enrichment of MHBs in predicted chromatin core 15-states using chromHMM [25, 63]: 1 TssA: Active Tss; 2 TssAFlnk: Flanking active TSS; 3 TxFlnk: Transcrption at gene 5′ and 3′; 4 EnhA: Active enhancer; 5 EnhAATAC: Active enhancer & ATAC; 6 EnhWk: Weak active enhancer; 7 EnhPois: Poised enhancer; 8 EnhPoisATAC: Poised enhancer & ATAC; 9 EnhWkCTCFATAC: Weak enhancer & CTCF & ATAC; 10 ATAC: ATAC islands; 11 reprWkCTCF: Weak represeed CTCF; 12 BivFlnk: Flanking bivalent TSS/Enhancer; 13 ReprRC: Repressed Polycomb; 14 ReprPCWk: Weak repressed Polycomb; and 15 Quies: Quiescent/Low. f One example of MHB located in the exon 4 of predicted maternal imprinted gene GAREM1 .…”

Integrating RNA-Seq with GWAS reveals novel insights into the molecular mechanism underpinning ketosis in cattle

“…This finding strongly suggests a highly polygenetic architecture underlying ketosis. Previous studies proposed that genetic variants of complex traits are enriched in genes with similar biological functions (e.g., Gene Ontology terms) [14][15][16][17][18]. For instance, McCabe et al (2012) previously demonstrated that differentially expressed genes (DEGs) induced by different energy conditions (i.e., mild NEB and severe NEB) were significantly engaged in fatty acid metabolism and steroid hormone biosynthesis [19].…”