RT Journal
A1 Wang, Liangxi
A1 Taylor, Tiegh
A1 Rathnakumar, Kumaragurubaran
A1 Khyzha, Nadiya
A1 Liang, Minggao
A1 Alizada, Azad
A1 Campitelli, Laura F.
A1 Pour, Sara E.
A1 Patel, Zain M.
A1 Antounians, Lina
A1 Tobias, Ian C.
A1 Hou, Huayun
A1 Hughes, Timothy R.
A1 Roy, Sushmita
A1 Mitchell, Jennifer A.
A1 Fish, Jason E.
A1 Wilson, Michael D.
T1 Multi-species analysis of inflammatory response elements reveals ancient and lineage-specific contributions of transposable elements to NF-kB binding
JF Genome Research 
JO Genome Research 
YR 2025 
FD July 01 
VO 35 
IS 7 
SP 1544 
OP 1559 
DO 10.1101/gr.280357.124 
UL http://genome.cshlp.org/content/35/7/1544.abstract 
AB 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.