Widespread contribution of transposable elements to the rewiring of mammalian 3D genomes and gene regulation

Abstract

Transposable elements (TEs) are major contributors of genetic material in mammalian genomes. These often include binding sites for architectural proteins, including the multifarious master protein, CTCF. These TE-derived architectural protein binding sites shape the 3D genome by creating loops, domains, and compartments borders as well as RNA-DNA chromatin interactions, all of which play a role in the compact packaging of DNA in the nucleus and have the potential to facilitate regulatory function.In this study, we explore the widespread contribution of TEs to mammalian 3D genomes by quantifying the extent to which they give rise to loops and domain border differences across various cell types and species using a variety of 3D genome mapping technologies. We show that specific (sub-)families of TEs have significantly contributed to lineage-specific 3D chromatin structures in specific mammals. In many cases, these loops have the potential to facilitate interaction between distant cis-regulatory elements and target genes, and domains have the potential to segregate chromatin state to impact gene expression in a lineage-specific and cell-type-specific manner. Backing our extensive conformation study cataloguing and computational analyses, we perform experimental validation using CRISPR-Cas9 to delete one such candidate TE and show disruption of species-specific 3D chromatin structure.Taken together, we comprehensively quantify and selectively validate our finding that TEs contribute significantly to 3D genome organization and continuously shape it to affect gene regulation during the course of mammalian evolution over deep time.

In silico discovery of repetitive elements as key sequence determinants of 3D genome folding

“…We observe both loss and gain of contact upon transposable element deletion, supporting the idea that these elements can both establish new boundaries by installing CTCF-like motifs and inhibit ancient CTCF binding sites to block contact [37]. Our results are also consistent with previous findings that specific MIR elements and tRNAs can serve as insulators [48,49], while Alu and hAT provide loop anchors [50,51], and hint that repetitive elements may work in tandem [42]. We are curious to test coordination of transposable elements as shadow loop anchors, theorized by Choudhary et al to act as redundant regulatory material supporting CTCF [37].…”

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

“…The majority of MER81derived RELA-bound regions are species-specific (79%) indicating the ancient MER81 elements may play core NF-κB functions in a human-specific manner. Growing evidence has indicated that TEs, especially evolutionarily young TEs, act as a potent source of cis-regulatory elements, which primarily innovate regulatory programs in a species-and tissue-specific manner (Buecker and Wysocka 2012;Chuong et al 2016;Fuentes et al 2018;Todd et al 2019;Choudhary et al 2022;Du et al 2022;Kelly et al 2022;Lee et al 2022). On the other hand, ancient TEs, though few, are also able to shape regulatory landscapes through either species-specific (Notwell et al 2015) or conserved mechanisms (Lynch et al 2011).…”

The Role of Transposable Elements in Sexual Development

“…Furthermore, TE insertions can promote new transcription factor (TF) binding sites, as well as coopt new enhancer elements and nuclear receptor response elements. These include binding sites for architectural proteins which confer widespread contribution to the dimensionality of the genome, as have been supported in computational models and validated through CRISPR-Cas9 experiments ( Choudhary et al, 2022 ).…”