Pig genome functional annotation enhances the biological interpretation of complex traits and human disease

Pan, Zhangyuan; Yao, Yuelin; Yin, Hongwei; Cai, Zexi; Wang, Ying; Bai, Liang; Kern, Colin; Halstead, Michelle M.; Chanthavixay, Ganrea; Trakooljul, Nares; Wimmers, Klaus; Sahana, Goutam; Su, Guosheng; Lund, Mogens Sandø; Fredholm, Merete; Karlskov-Mortensen, Peter; Ernst, Catherine W.; Ross, Pablo J.; Tuggle, Christopher K.; Fang, Lingzhao; Zhou, Huaijun

doi:10.1038/s41467-021-26153-7

Cited by 102 publications

(148 citation statements)

References 91 publications

(112 reference statements)

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“…Previous studies have provided powerful evidence for the crucial roles of cis‐regulatory elements (CREs) in identifying causative variants of complex traits 16,72,73 . With driven efforts by FAANG, a growing body of studies engaged in the functional annotation of farm animal genome have emerged, further leading to characterize the genetic architecture of important economic traits and enhance the animal performance 20,22,74,75 . Although major advances have been made in bovine epigenome study, the epigenetic basis for foetal skeletal muscle development remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional states and chromatin accessibility during bovine myoblasts proliferation and myogenic differentiation

Wang

et al. 2022

Cell Proliferation

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Objectives: Although major advances have been made in bovine epigenome study, the epigenetic basis for fetal skeletal muscle development still remains poorly understood. The aim is to recapitulated the time course of fetal skeletal muscle development in vitro, and explore the dynamic changes of chromatin accessibility and gene expression during bovine myoblasts proliferation and differentiation.Methods: PDGFR-cells were isolated from bovine fetal skeletal muscle, then cultured and induced myogenic differentiation in vitro in a time-course study (P, D0, D2, and D4). The assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed.Results: Among the enriched transcriptional factors with high variability, we determined the effects of MAFF, ZNF384, and KLF6 in myogenesis using RNA interference (RNAi). In addition, we identified both stage-specific genes and chromatin accessibility regions to reveal the sequential order of gene expression, transcriptional regulatory, and signal pathways involved in bovine skeletal muscle development. Further investigation integrating chromatin accessibility and transcriptome data was conducted to explore cis-regulatory regions in line with gene expression. Moreover, we combined bovine GWAS results of growth traits with regulatory regions defined by chromatin accessibility, providing a suggestive means for a more precise annotation of genetic variants of bovine growth traits. Conclusion:Overall, these findings provide valuable information for understanding the stepwise regulatory mechanisms in skeletal muscle development and conducting beef cattle genetic improvement programs. | INTRODUCTIONSkeletal muscle, which accounts for about 40% of total body weight, 1 is a highly dynamic tissue of the body. The growth and maintenance of skeletal muscle play an important role in crucial Qian Li and Yahui Wang contributed equally to this work and shared the first authorship.

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Section: Discussionmentioning

confidence: 99%

Transcriptional states and chromatin accessibility during bovine myoblasts proliferation and myogenic differentiation

Wang

et al. 2022

Cell Proliferation

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“…In addition, we further investigated the enrichment of SINE families in 15 distinct chromatin states across 14 tissues ( Fig. 2d , Supplementary Information) 68 . We observed that young SINE groups (youngest and younger) show lower enrichment in most of the functional chromatin states than old SINE groups (older and oldest), and the enrichment degree of SINE in chromatin states was roughly similar across 14 tissues.…”

Section: Resultsmentioning

confidence: 99%

Building an atlas of transposable elements reveals the extensive roles of young SINE in gene regulation, genetic diversity, and complex traits in pigs

Zhao

Gao

et al. 2022

Preprint

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Transposable elements (TEs) are an extensive source of genetic polymorphisms and play an indispensable role in chromatin architecture, transcriptional regulatory networks, and genomic evolution. The pig is an important source of animal protein and serves as a biomedical model for humans, yet the functional role of TEs in pigs and their contributions to complex traits are largely unknown. Here, we built a comprehensive catalog of TEs (n = 3,087,929) in pigs by a newly developed pipeline. Through integrating multi-omics data from 21 tissues, we found that SINEs with different ages were significantly associated with genomic regions with distinct functions across tissues. The majority of young SINEs were predominantly silenced by histone modifications, DNA methylation, and decreased accessibility. However, the expression of transcripts that were derived from the remaining active young SINEs exhibited strong tissue specificity through cross-examining 3,570 RNA-seq from 79 tissues and cell types. Furthermore, we detected 211,067 polymorphic SINEs (polySINEs) in 374 individuals genome-wide and found that they clearly recapitulated known patterns of population admixture in pigs. Out of them, 340 population-specific polySINEs were associated with local adaptation. Mapping these polySINEs to genome-wide associations of 97 complex traits in pigs, we found 54 candidate genes (e.g., ANK2 and VRTN) that might be mediated by TEs. Our findings highlight the important roles of young SINEs in functional genomics and provide a supplement for genotype-to-phenotype associations and modern breeding in pigs.

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“…These data provided information about the regulatory element status of the region based on enrichment of histone marks (H3K27me3, H3K4me1, H3K27ac, H3K4me3), ATAC-Seq and CTCF data in 15 tissues of two male Bos taurus . The method to classify the genomic region regarding the regulatory element state was described by Pan et al [ 70 ]. In summary, the epigenetic marks data described above were used to train a chromatin state prediction model in ChromHMM69 (v.1.20) and 15 states were chosen.…”

Section: Methodsmentioning

confidence: 99%

DNA methylation may affect beef tenderness through signal transduction in Bos indicus

Souza

Niciura

Rocha

et al. 2022

Epigenetics & Chromatin

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Background Beef tenderness is a complex trait of economic importance for the beef industry. Understanding the epigenetic mechanisms underlying this trait may help improve the accuracy of breeding programs. However, little is known about epigenetic effects on Bos taurus muscle and their implications in tenderness, and no studies have been conducted in Bos indicus. Results Comparing methylation profile of Bos indicus skeletal muscle with contrasting beef tenderness at 14 days after slaughter, we identified differentially methylated cytosines and regions associated with this trait. Interestingly, muscle that became tender beef had higher levels of hypermethylation compared to the tough group. Enrichment analysis of predicted target genes suggested that differences in methylation between tender and tough beef may affect signal transduction pathways, among which G protein signaling was a key pathway. In addition, different methylation levels were found associated with expression levels of GNAS, PDE4B, EPCAM and EBF3 genes. The differentially methylated elements correlated with EBF3 and GNAS genes overlapped CpG islands and regulatory elements. GNAS, a complex imprinted gene, has a key role on G protein signaling pathways. Moreover, both G protein signaling pathway and the EBF3 gene regulate muscle homeostasis, relaxation, and muscle cell-specificity. Conclusions We present differentially methylated loci that may be of interest to decipher the epigenetic mechanisms affecting tenderness. Supported by the previous knowledge about regulatory elements and gene function, the methylation data suggests EBF3 and GNAS as potential candidate genes and G protein signaling as potential candidate pathway associated with beef tenderness via methylation.

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Pig genome functional annotation enhances the biological interpretation of complex traits and human disease

Cited by 102 publications

References 91 publications

Transcriptional states and chromatin accessibility during bovine myoblasts proliferation and myogenic differentiation

Transcriptional states and chromatin accessibility during bovine myoblasts proliferation and myogenic differentiation

Building an atlas of transposable elements reveals the extensive roles of young SINE in gene regulation, genetic diversity, and complex traits in pigs

DNA methylation may affect beef tenderness through signal transduction in Bos indicus

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