Abstract
Chromatin looping is important for gene regulation, and studies of 3D chromatin structure across species and cell types have improved our understanding of the principles governing chromatin looping. However, 3D genome evolution and its relationship with natural selection remains largely unexplored. In mammals, the CTCF protein defines the boundaries of most chromatin loops, and variations in CTCF occupancy are associated with looping divergence. While many CTCF binding sites fall within transposable elements (TEs), their contribution to 3D chromatin structural evolution is unknown. Here we report the relative contributions of TE-driven CTCF binding site expansions to conserved and divergent chromatin looping in human and mouse. We demonstrate that TE-derived CTCF binding divergence may explain a large fraction of variable loops. These variable loops contribute significantly to corresponding gene expression variability across cells and species, possibly by refining sub-TAD-scale loop contacts responsible for cell-type-specific enhancer-promoter interactions.
Highlights
Human only Mouse −2070 Transposable element types Mouse onlyGM12878 K562 CH12 MELBinomial P -value < 2e-16 0.5 log-2 count -log[2] freq Shared
The results show that transposable elements (TEs) have contributed strongly to CTCF binding in both species, constituting ~35% of all CTCFbinding sites
Most studies have focused on the impact of CTCF-enriched TE types to the genome, we find evidence that all TE types with an embedded CTCF motif may affect chromatin looping, and that the genomic magnitude of their effects reflects their abundance and the strength of the CTCF motif they carry
Summary
Our ultimate goal was to investigate the impact of transposable element activity on chromatin looping divergence. We used publicly available ChIP-seq, ChIA-PET, and Hi-C data to identify chromatin loops in the human and mouse genomes, in which at least one anchor was derived from a transposable element. We further investigated the properties and potential effects of TE-driven loop divergence by identifying sets of loops, in which a species-specific TE insertion created a differential loop (Fig. 1). TE-derived CTCF sites are prevalent in human and mouse. We first assessed the genome-wide effects of TE proliferation on CTCF binding in human and mouse. CTCF ChIP-seq data for matched immune cell types from both species (Source Data File) were combined into a union set of orthologous and speciesspecific binding sites and intersected with known TE insertions[50] (Fig. 2a).
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