Ruminant-specific retrotransposons shape regulatory evolution of bovine immunity

Abstract

Cattle are an important livestock species, and mapping the genomic architecture of agriculturally relevant traits such as disease susceptibility is a major challenge in the bovine research community. Lineage-specific transposable elements (TEs) are increasingly recognized to contribute to gene regulatory evolution and variation, but this possibility has been largely unexplored in ruminant genomes. We conducted epigenomic profiling of the type II interferon (IFN) response in bovine cells, and found thousands of ruminant-specific TEs including MER41_BT and Bov-A2 elements predicted to act as IFN-inducible enhancer elements. CRISPR knockout experiments in bovine cells established that critical immune factors including IFNAR2 and IL2RB are transcriptionally regulated by TE-derived enhancers. Finally, population genomic analysis of 39 individuals revealed that a subset of TE-derived enhancers represent polymorphic insertion sites in modern cattle. Our study reveals that lineage-specific TEs have shaped the evolution of ruminant IFN responses, and potentially continue to contribute to immune gene regulatory differences across modern breeds and individuals. Together with previous work in human cells, our findings demonstrate that lineage-specific TEs have been independently co-opted to regulate IFN-inducible gene expression in multiple species, supporting TE co-option as a recurrent mechanism driving the evolution of IFN-inducible transcriptional networks.

Transcriptional dynamics of transposable elements in the type I IFN response in Myotis lucifugus cells

“…Unexpectedly, while our RNA-seq analysis of M. lucifugus cells coincided with strong transcriptional response to IFN treatment, we observed relatively modest chromatin changes based on CUT&RUN epigenomic profiling. This observation contrasts with robust chromatin changes typically observed in IFN-treated cells from other mammalian species [22,53,54]. As a result, we did not observe strong evidence supporting family-level TE regulatory induction as observed previously in other species such as human [50] and cow [22], partly due to the lack of clearly inducible elements at a genome-wide level.…”

“…4). However, in contrast to previous studies in other species [22][23][24][25][26], we did not observe any overrepresented TE families within this set (Fig. S3B; Table S12).…”

“…Unexpectedly, we did not observe robust IFN-inducible chromatin changes that are characteristic of IFN-stimulated cells from other species [22,50]. We did not identify any H3K27ac inducible elements with an FDR < 0.05 (Fig.…”

“…5A). Using spike-in normalized CUT&RUN data at 0 and 4h, we used DESeq2 to define IFN-inducible regulatory elements, as performed previously [22].…”

“…TE-derived non-coding transcripts can readily form immunostimulatory double-strand RNAs or DNAs [19][20][21]. Finally, TEs can regulate interferon-4 inducible gene expression by acting as regulatory elements [22][23][24][25][26]. The recurrent co-option of TEs for immune functions throughout evolution may reflect their capacity to fuel adaptation by increasing genomic variation, especially in the context of host-pathogen coevolutionary arms races [27,28].…”