Identification of cis-regulatory elements provides insights into tissue-specific gene regulation in the sheep genome
Annotation of regulatory elements is essential for understanding mechanisms underlying gene regulation, particularly tissue-specific regulation in human and animals. Here, we characterize 274,682 enhancers and 25,975 promoters across 24 tissues from an adult female sheep using ChIP-seq, ATAC-seq, CAGE-seq, RRBS, WGBS, and RNA-seq. We identify seven neural development-related genes with over 10 enhancers in brain tissues, highlighting the role of tissue-specific regulation. Cis-regulatory enhancer-promoter combinations provide insights into tissue-specific enhancers, such as the cerebellum-specific enhancer (chr15: 57390520-57390685) regulating BDNF, which is expressed in both the cerebellum and cerebral cortex. Comparative analysis of enhancer-promoter combinations in human, mouse, pig, cattle, and sheep reveals ruminant-specific pathways, including pentose catabolism and long-chain fatty acid import regulation. A milk fat yield quantitative trait locus (QTL) identified within an enhancer interacts with the fat metabolism-related gene COMMD1, and a birth weight-associated QTL detected within a cerebellum-specific enhancer regulates XKR4. This study provides a robust framework for exploring cis-regulatory mechanisms and tissue-specific regulation, advancing the functional annotation of the sheep reference genome.
Authors
- Shannon Clarke (ORCID: https://orcid.org/0000-0002-4615-8917)
- Alex Caulton (ORCID: https://orcid.org/0000-0003-3193-1484)
- Emily L. Clark (ORCID: https://orcid.org/0000-0002-9550-7407)
- Rüdiger Bräuning (ORCID: https://orcid.org/0000-0001-5068-9166)
- Stephen N. White (ORCID: https://orcid.org/0000-0001-9255-6054)
- Alisha T. Massa (ORCID: https://orcid.org/0000-0002-5098-7494)
- Temitayo Olagunju (ORCID: https://orcid.org/0000-0002-1497-6173)
- Mazdak Salavati (ORCID: https://orcid.org/0000-0002-7349-2451)
- Kimberly M Davenport (ORCID: https://orcid.org/0000-0003-2796-9252)
- Timothy P. L. Smith (ORCID: https://orcid.org/0000-0003-1611-6828)
- Michelle R. Mousel (ORCID: https://orcid.org/0000-0003-1367-7005)
- Brenda M. Murdoch (ORCID: https://orcid.org/0000-0001-8675-3473)
- Gordon K. Murdoch (ORCID: https://orcid.org/0000-0002-8643-7777)
- Stephanie McKay (ORCID: https://orcid.org/0000-0003-1434-3111)
- Gabrielle M. Becker (ORCID: https://orcid.org/0000-0002-1455-6443)
- Katie A Shira (ORCID: https://orcid.org/0000-0002-2289-440X)
- Benjamin D. Rosen (ORCID: https://orcid.org/0000-0001-9395-8346)
- N. E. Cockett
- Sarem F. Khilji (ORCID: https://orcid.org/0000-0002-9139-9760)
- Shangqian Xie
- Kim Worley
- Alan Archibald
- Tracy Hadfield
- Morgan R. Stegmiller
Institutions
- Utah State University (US)
- Roslin Institute (GB)
- University of Idaho (US)
- Baylor College of Medicine (US)
- AgResearch (NZ)
- Beltsville Agricultural Research Center (US)
- Roman L. Hruska U.S. Meat Animal Research Center (US)
- Genus (United States) (US)
- Washington State University (US)
- University of Missouri (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-16
- DOI
- https://doi.org/10.1038/s41467-026-70382-7
- Primary Topic
- Genetic Mapping and Diversity in Plants and Animals
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Agriculture
- National Institute of Food and Agriculture