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. 2020 Jan 24;21(1):16.
doi: 10.1186/s13059-019-1916-8.

Co-opted Transposons Help Perpetuate Conserved Higher-Order Chromosomal Structures

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Free PMC article

Co-opted Transposons Help Perpetuate Conserved Higher-Order Chromosomal Structures

Mayank Nk Choudhary et al. Genome Biol. .
Free PMC article

Erratum in

Abstract

Background: Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed.

Results: Here, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time.

Conclusions: TEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.

Keywords: 3D genome; Binding site turnover; Conservation; Evolution; Loops; Transposable elements.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Contribution of repetitive elements (REs) to chromatin loops in humans and mouse. a Pie charts representing percentage of loops and b unique loop anchor CTCF sites derived from REs in a variety of human and mouse cell types. c Stacked bar plots showing the distribution of RE-derived anchor CTCF across major RE classes in the various human and mouse cell types. Stacked bar plots showcasing the distribution of RE-derived anchor CTCF vs. background and CTCF ChIP peaks across d major RE classes and e major RE families in matched blood lymphoblastoid cell line (mouse = CH12-LX; human = GM12878)
Fig. 2
Fig. 2
Contribution of TEs to the conservation landscape of human and mouse loops. a Flowchart describing the methodology used to annotate loop orthology. b Venn diagram representing the various classes of chromatin loops based on their orthology and bar plots showing the contribution of REs to anchor CTCFs of each class of loops. c Age distribution and age of individual TEs that contribute loop anchor CTCF sites (black dots for orthologous loops; gold dots for non-orthologous loops) (left), total contribution to loop anchor CTCF sites (middle), distribution of orthologous and non-orthologous loops (right) derived from the top 13 TE subfamilies in mouse and d humans. Estimated primate/rodent divergence time (82 million years ago) is from Meredith et al. [47]. e Contact maps representing a conserved chromatin loop in a syntenic region between human and mouse. f A MER20 transposon insertion provides a redundant CTCF motif that helps in maintaining the conserved 3D structure in mouse via CTCF binding site turnover with remnants of the ancestral CTCF motif, well conserved in most non-rodent mammals (Additional file 1: Figure S2), still seen in the mouse genome
Fig. 3
Fig. 3
TEs are necessary for maintaining conserved higher-order chromosomal structures in humans. a Results of a CRISPR/Cas9-based deletion of an L1M3f element at chr10:26–28 Mb in GM187278 cells. Mega-contact maps (details in “Methods”) generated using Hi-C2 technology for the (top) WT locus and (bottom) KO (ΔL1M3f) locus. b Virtual 4C plot displaying total percent interactions emanating from an anchor on a 5-kb window containing the L1M3f element. c Boxplot measuring the percent inter-domain interactions (Additional file 3: Table S2.5) across the targeted domain and a control domain (boundaries unaffected by CRISPR edits) using subsampled contact maps (details in “Methods”). d Results of CRISPR/Cas9-based deletion of an LTR41 element at chr8:70.3–71.8 Mb in GM12878 cells. Mega-contact maps generated in Hi-C2 experiments for the (top) WT locus and (bottom) KO (ΔLTR41) locus. e Virtual 4C plot displaying total percent interactions emanating from an anchor on a 5-kb window containing the left anchor CTCF of the conserved loop, and f the LTR41 element
Fig. 4
Fig. 4
Turnover TEs are hypomethylated through evolutionary time. a Methylation signature ± 2 kb around CTCF sites that help maintain orthologous loops segmented by the origin of the anchor CTCF site. b Methylation-associated and non-methylation mutational signature of individual TEs relative to its ancestral sequence in humans (mouse TE data available in Additional file 1: Figure S8). Alignments were performed using crossmatch (shown here) and Needle (details in “Methods”, results in Additional file 1: Figure S9). Error bars show one standard deviation of the means from 1000 simulations. c Schematic depicting the framework of TE-mediated CTCF binding site turnover that highlights the intimate reciprocity between the TE, genome, and epigenome, to help maintain conserved 3D genome structure

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