Analyzing super-enhancer temporal dynamics reveals potential critical enhancers and their gene regulatory networks underlying skeletal muscle development
- Song Zhang1,2,7,
- Chao Wang1,2,3,7,
- Shenghua Qin1,2,7,
- Choulin Chen1,2,3,
- Yongzhou Bao1,2,
- Yuanyuan Zhang1,2,
- Lingna Xu1,2,
- Qingyou Liu4,
- Yunxiang Zhao5,
- Kui Li1,2,6,
- Zhonglin Tang1,2,6 and
- Yuwen Liu1,2,6
- 1Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China;
- 2Innovation Group of Pig Genome Design and Breeding, Research Centre for Animal Genome, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China;
- 3Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China;
- 4Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Life Science and Engineering, Foshan University, Foshan 528225, China;
- 5Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning 530004, China;
- 6Kunpeng Institute of Modern Agriculture at Foshan, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Foshan 528226, China
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↵7 These authors contributed equally to this work.
Abstract
Super-enhancers (SEs) govern the expression of genes defining cell identity. However, the dynamic landscape of SEs and their critical constituent enhancers involved in skeletal muscle development remains unclear. In this study, using pig as a model, we employed cleavage under targets and tagmentation (CUT&Tag) to profile the enhancer-associated histone modification marker H3K27ac in skeletal muscle across two prenatal and three postnatal stages, and investigated how SEs influence skeletal muscle development. We identify three SE families with distinct temporal dynamics: continuous (Con, 397), transient (TS, 434), and de novo (DN, 756). These SE families are associated with different temporal gene expression trajectories, biological functions, and DNA methylation levels. Notably, several lines of evidence suggest a potential prominent role of Con SEs in regulating porcine muscle development and meat traits. To pinpoint key cis-regulatory units in Con SEs, we developed an integrative approach that leverages information from eRNA annotation, genome-wide association study (GWAS) signals, and high-throughput capture self-transcribing active regulatory region sequencing (STARR-seq) experiments. Within Con SEs, we identify 20 candidate critical enhancers with meat and carcass-associated DNA variations that affect enhancer activity, and infer their upstream transcription factors and downstream target genes. As a proof of concept, we experimentally validate the role of one such enhancer and its potential target gene during myogenesis. Our findings reveal the dynamic regulatory features of SEs in skeletal muscle development and provide a general integrative framework for identifying critical enhancers underlying the formation of complex traits.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.278344.123.
- Received July 29, 2023.
- Accepted October 15, 2024.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
