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

Abstract

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is an essential and evolutionarily conserved transcription factor complex primarily involved in innate immunity and inflammation. Transposable elements (TEs) can be co-opted to innovate immune transcriptional regulatory networks; however, the extent to which TEs have contributed to the modulation of NF-κB response in different mammalian lineages is not well established. Here we performed a multi-species analysis of TEs bound by the NF-κB subunit RELA (p65) in response to the pro-inflammatory cytokine TNFα (Tumor Necrosis Factor alpha). Using endothelial cell RELA ChIP-seq data from human, mouse and cow, we found that 55 TE subfamilies were enriched within NF-κB bound regions. These RELA-bound transposons possess multiple active epigenetic features and reside near TNFα-induced 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 NF-κB bound regions in cow. By comparing NF-κB binding data across species, we found several examples of NF-κB motif-bearing TEs that appeared to colonize the genome prior to the divergence of the selected mammals, including a DNA transposon MER81, whose ancestral sequence contains two intact RELA motifs. We demonstrate that one NF-κB bound MER81 element can control the TNFα-induced expression of INFGR2 (Interferon Gamma Receptor 2) in human. Lastly, the presence of RELA motifs within MER81 elements appeared to stabilize during human evolution, indicative of purifying selection acting on a subset of these NF-κB bound ancient DNA transposons. Taken together, our results implicate multiple transposons in establishing NF-κB mediated regulatory networks during mammalian evolution.

Differential selective regimes identify categories of transposable elements with regulatory function

“…1) we noted the presence of 11 out of the 14 TE subfamilies shown in 6 to be epigenetically activated upon bacterial infection (MER41B, MER44B, MLT1F/H/I/K/L, THE1B/C, and Tigger3a/b - all of them being found under significant selection when overlapping dELS and/or chromHMM regulatory regions). Some significant TE categories are also likely to be involved in immune response through the rewiring of the NF-κB regulome 7 , including again MER41B and MER44B. The ERV1 family, which was shown to be associated with TP53 binding sites 25 , was found to be under selection when overlapping ChromHMM and dELS regulatory regions.…”

“…1 Widespread exaptation of AmnSINE1 elements has been associated with the emergence of mammalian-specific traits, specifically in brain development 20,21 . Both AmnSINE1 and MamSINE1 were found enriched in active regulatory regions in human development 22 , and to be involved in the rewiring of the NF-κB regulome 7 , while MIR3 and MIRc were shown to contribute to gene regulation in decidual stromal cells in mammals 23 and the regulome of estrogen receptor alpha 24 .…”

“…Transposable elements (TEs) have been shown to provide raw material for the rapid evolution of genomes, and specifically of gene regulation, by creating quickly dispersing genetic elements potentially exploitable by the host as binding sites for DNA-binding factors involved in regulating transcription and three-dimensional genome conformation (see [1][2][3] for recent reviews), in a phenomenon called TE exaptation. Human regulatory network rewiring by TE exaptation has been recently shown to be relevant to a variety of biological processes, including in particular immune response [4][5][6][7] , germ cell development 8,9 , longevity 10 , pluripotency 11 , and 3D genome conformation 12 . TE exaptation can be used by the host not only to rewire the regulatory network by providing new regulatory targets of transcription factors (TFs), but also to increase the robustness of the existing regulatory network by providing additional, redundant binding sites near existing ones [13][14][15] .…”