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

Authors: FANG, LINGZHAO - University Of Edinburgh; LIU, SHULI - China Agricultural University; LIU, MEI - Northwest Agriculture And Forestry University; KANG, XIAOLONG - Ningxia University; LIN, SHUDAI - South China Agricultural University; LI, BINGJIE - Oak Ridge Institute For Science And Education (ORISE); Connor, Erin; Baldwin, Ransom - Randy; TENESA, ALBERT - University Of Edinburgh; MA, LI - University Of Maryland; Liu, Ge - George; Li, Congjun - Cj

Submitted to: BMC Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/5/2019
Publication Date: 8/16/2019
Citation: Fang, L., Liu, S., Liu, M., Kang, X., Lin, S., Li, B., Connor, E.E., Baldwin, R.L., Tenesa, A., Ma, L., Liu, G., Li, C. 2019. Functional annotation of the cattle genome through systematic discovery and characterization of chromatin states and butyrate-induced variations. BMC Biology. 17(1):68. https://doi.org/10.1186/s12915-019-0687-8.
DOI: https://doi.org/10.1186/s12915-019-0687-8

Interpretive Summary: We established the first global map of genomic regulatory elements (15 chromatin states) and defined their coordinated activities in cattle, through genome-wide profiling using high-throughput-sequencing technologies for six histone modifications, RNA polymerase II, CTCF-binding sites, DNA accessibility, DNA methylation, and transcriptome in rumen epithelial primary cells. Our results determined the essential role of functional genome elements for understanding genome regulation in livestock.

Technical Abstract: The lack of functional annotation of genomes hinders the biological interpretation for complex trait variation, domestication, and adaptive evolution in livestock. Here 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, gene expression and methylation across tissues, trait-associated variants, eQTLs, selection signatures, and evolutionarily conserved elements, implying distinct biological functions. After butyrate (a key regulator for rumen development) treatments, we observed that the weak enhancers and flanking regions of 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. 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.