Integrative mapping of the dog epigenome: reference annotation for comparative inter-tissue and cross-species studies

Abstract

The domestic dog has become a valuable model in exploring multifaceted diseases and biology important for human health. Large-scale dog genome projects produced high-quality draft references but still lack comprehensive annotation of encoded functional elements. Through the integrative next generation sequencing of transcriptomes paired with histone marks and DNA methylome profiling of 11 adult tissue types, implemented in a cross-species approach, we generated a reference epigenome of a domesticated dog. Using genome orthologues and synthenies, we deciphered the dog's epigenetic code by defining distinct chromatin states, allowing for genome-wide, integratable data production. We then characterized somatic super-enhancer landscapes and showed that genes mapped on these regions are associated with a broad range of biological and disease traits and are traceable to their tissue-of-origin. Ultimately, we delineated conserved epigenomic changes at the tissue- and species-specific resolutions. Our study provides an epigenomic blueprint of the dog for comparative biology and medical research.

Comparative oncology: overcoming human cancer through companion animal studies

“…Our recent studies involving genomic and epigenomic comparisons across tissues of different species also revealed that chromatin map overlaps more between canines and humans (~40-50%) than between mice and humans (~10-20%). Furthermore, we also found that super enhancers were more highly conserved between canines and humans (~90% at ~50% minimum mismatch ratio) than between humans and mice (~30% at ~50% minimum mismatch ratio) 21 . Thus, the epigenetic changes affected by the environment might be more similar between canines and humans than between mice and humans.…”

DNA methylation and chromatin accessibility predict age in the domestic dog

“…To assess global properties of the ATAC and methylation datasets, we performed feature level analysis on individual ATAC‐seq peaks and RRBS‐seq DNAm sites (15,417 ATAC peaks and 13,336 CpG sites after quality control filtering, see Section 4: Methods). First, we mapped each locus to the Epigenome Catalog of the Dog, a multi‐tissue canine chromatin state map (EpiC Dog; Son et al., 2023) to approximate a functional annotation for each feature. EpiC Dog is a curated repository of regulatory elements across chromatin datasets collected from 11 different tissue types in the companion dog (Figure S2a; Son et al., 2023).…”

“…First, we mapped each locus to the Epigenome Catalog of the Dog, a multi‐tissue canine chromatin state map (EpiC Dog; Son et al., 2023) to approximate a functional annotation for each feature. EpiC Dog is a curated repository of regulatory elements across chromatin datasets collected from 11 different tissue types in the companion dog (Figure S2a; Son et al., 2023). PBMCs were not profiled in EpiC Dog, so we chose to compare to the annotations from canine spleen tissue.…”

Exosome proteomes reveal glycolysis-related enzyme enrichment in primary tumors

“…Thus we used canine mammary gland tumor cell lines; CHMp for primary tumor and CHMm for metastases (derived from metastatic lung pleural effusion) originated from same individual [24]. Canine breast cancer cell lines CHMp and CHMm are used due to its natural occurrence and the gene regulatory sequence of dogs is more similar to humans than mice [19,25].…”

“…Glycolysis is a key metabolic pathway involved in energy production and biosynthesis in cancer cells [24]. Additionally, glycolysis is closely associated with tumor metastasis [25]. Exosomemediated metabolic reprogramming has been shown to play a crucial role in tumor microenvironment formation and tumor progression [26].…”