Multi-species analysis of inflammatory response elements reveals ancient and lineage-specific contributions of transposable elements to NF-kB binding

Liangxi Wang; Tiegh Taylor; Kumaragurubaran Rathnakumar; Nadiya Khyzha; Minggao Liang; Azad Alizada; Laura F. Campitelli; Sara E. Pour; Zain M. Patel; Lina Antounians; Ian C. Tobias; Huayun Hou; Timothy R. Hughes; Sushmita Roy; Jennifer A. Mitchell; Jason E. Fish; Michael D. Wilson

doi:10.1101/gr.280357.124

Multi-species analysis of inflammatory response elements reveals ancient and lineage-specific contributions of transposable elements to NF-kB binding

¹Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3K3, Canada;
²Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario M5G 0A4, Canada;
³Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur and Centre National pour la Recherche Scientifique (CNRS), Valbonne 06560, France;
⁴Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada;
⁵Division of Developmental Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA;
⁶Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada;
⁷Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3K3, Canada;
⁸Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA;
⁹Department of Comprehensive Pathology, Institute of Science Tokyo, Tokyo 108-0071, Japan;
¹⁰Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario M5S 3E1, Canada;
¹¹Developmental and Stem Cell Biology, SickKids Research Institute, Toronto, Ontario M5G 0A4, Canada;
¹²Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada;
¹³Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin 53726, USA;
¹⁴Wisconsin Institute for Discovery, Madison, Wisconsin 53715, USA;
¹⁵Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario M5G 2N2, Canada

↵Present addresses: ¹⁶Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford OX3 7TY, UK; ¹⁷Department of Biomedical Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada

Corresponding author: michael.wilson{at}sickkids.ca

Abstract

Transposable elements (TEs) provide a source of transcription factor (TF) binding sites that can rewire gene regulatory networks. NF-kB is an evolutionarily conserved TF complex primarily involved in innate immunity and inflammation. The extent to which TEs have contributed to NF-kB responses during mammalian evolution is not well established. Here, we perform a multi-species analysis of TEs bound by the NF-kB subunit RELA in response to the proinflammatory cytokine TNF. By comparing RELA ChIP-seq data from TNF-stimulated primary aortic endothelial cells isolated from human, mouse, and cow, we find that 55 TE subfamilies are associated with RELA-bound regions, many of which reside near TNF-responsive genes. A prominent example of lineage-specific contribution of transposons comes from the bovine SINE subfamilies Bov-tA1/2/3 which collectively contributed over 14,000 RELA-bound regions in cow. By comparing RELA binding data across species, we also find several examples of RELA motif-bearing TEs that colonized the genome prior to the divergence of the three species and contributed to species-specific RELA binding. For example, we find human RELA-bound MER81 instances are enriched for the interferon gamma pathway and demonstrate that one RELA-bound MER81 element can control the TNF-induced expression of interferon gamma receptor 2 (IFNGR2). Using ancestral reconstructions, we find that RELA containing MER81 instances rapidly decayed during early primate evolution (>50 million years ago [MYA]) before stabilizing since the separation of Old World monkeys (<50 MYA). Taken together, our results suggest ancient and lineage-specific transposon subfamilies contributed to mammalian NF-kB regulatory networks.

Footnotes

[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.280357.124.

Received December 19, 2024.
Accepted April 23, 2025.

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