CNEReg Interprets Ruminant-specific Conserved Non-coding Elements by Developmental Gene Regulatory Network

Xiangyu Pan; Zhaoxia Ma; Xinqi Sun; Hui Li; Tingting Zhang; Chen Zhao; Nini Wang; Rasmus Heller; Wing Hung Wong; Wen Wang; Yu Jiang; Yong Wang

doi:10.1016/j.gpb.2022.11.007

CNEReg Interprets Ruminant-specific Conserved Non-coding Elements by Developmental Gene Regulatory Network

Genomics Proteomics Bioinformatics. 2023 Jun;21(3):632-648. doi: 10.1016/j.gpb.2022.11.007. Epub 2022 Dec 7.

Authors

Xiangyu Pan¹, Zhaoxia Ma², Xinqi Sun², Hui Li³, Tingting Zhang⁴, Chen Zhao⁴, Nini Wang⁴, Rasmus Heller⁵, Wing Hung Wong⁶, Wen Wang⁷, Yu Jiang⁸, Yong Wang⁹

Affiliations

¹ Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; Department of Medical Research, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
² Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China; School of Mathematics, University of Chinese Academy of Sciences, Beijing 100049, China.
³ Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning 530005, China.
⁴ Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
⁵ Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen DK-2100, Denmark.
⁶ Department of Statistics, Department of Biomedical Data Science, Bio-X Program, Stanford University, Stanford, CA 94305, USA.
⁷ Center for Ecological and Environmental Sciences, Northwestern Polytechnical University, Xi'an 710072, China; State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China. Electronic address: wwang@mail.kiz.ac.cn.
⁸ Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China. Electronic address: yu.jiang@nwafu.edu.cn.
⁹ Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China; School of Mathematics, University of Chinese Academy of Sciences, Beijing 100049, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: ywang@amss.ac.cn.

Abstract

The genetic information coded in DNA leads to trait innovation via a gene regulatory network (GRN) in development. Here, we developed a conserved non-coding element interpretation method to integrate multi-omics data into gene regulatory network (CNEReg) to investigate the ruminant multi-chambered stomach innovation. We generated paired expression and chromatin accessibility data during rumen and esophagus development in sheep, and revealed 1601 active ruminant-specific conserved non-coding elements (active-RSCNEs). To interpret the function of these active-RSCNEs, we defined toolkit transcription factors (TTFs) and modeled their regulation on rumen-specific genes via batteries of active-RSCNEs during development. Our developmental GRN revealed 18 TTFs and 313 active-RSCNEs regulating 7 rumen functional modules. Notably, 6 TTFs (OTX1, SOX21, HOXC8, SOX2, TP63, and PPARG), as well as 16 active-RSCNEs, functionally distinguished the rumen from the esophagus. Our study provides a systematic approach to understanding how gene regulation evolves and shapes complex traits by putting evo-devo concepts into practice with developmental multi-omics data.

Keywords: Conserved non-coding element; Gene regulatory network; Ruminant; Toolkit transcription factor; Trait innovation.

MeSH terms

Animals
Gene Expression Regulation
Gene Expression Regulation, Developmental
Gene Regulatory Networks*
Ruminants / genetics
Ruminants / metabolism
Sheep / genetics
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Transcription Factors