Investigation Of The Potential Function Of Retrocopies In The 3D Chromatin Architecture Of The Human And Mouse Genomes

Retrocopies generated by the mechanism of RNA-mediated retrotransposition are thought to be a key genetic material that contributes substantially to genome evolution and phenotypic adaptation in various species.High-resolution chromatin contact maps not only provide detailed information about the higher-order chromatin structure of a cell type but also can be used to interrogate the potential function of different genomic elements in three dimensional(3D)genome,and recent studies have reported the biology of several types of transposable elements in the context of higher-order chromatin structure.However,it is unclear whether retrocopies may have played an important role in the 3D chromatin organization of mammalian genomes because relevant studies are mostly focused on their function and evolution at the single-gene level.To address this issue,for the first time this study integrated information on parent-retrocopy pairs,interacting chromatin contact maps,topologically associating domains(TADs),histone modification,CCCTC-binding factor(CTCF)binding sites and syntenic relationships of genomic regions between humans and mice and systematically studied the potential role of retrocopies in the 3D architecture of genomes.Mapping parent-retrocopy pairs onto interacting chromatin contacts in human and mouse cell lines revealed that the retrocopies exhibit more frequent spatial colocalization with their parental genes than would be expected by chance.Additionally,to illustrate the biased distribution of the retrocopies relative to TAD boundaries,this study partitioned the genomic regions around TAD boundaries into non-overlapping 200 kb windows and counted the number of retrocopies in each window.Significantly,the retrocopies are generally nearer to TAD boundaries than random genomic fragments.Our analysis suggested that retrocopies may play a role in 3D genome structure.A serious of comparison of the distance from colocalized or noncolocalized retrocopies to the nearest TAD boundaries in human and mouse cell lines showed that the colocalized retrocopies were significantly closer to the nearest TAD boundaries.Furthermore,this study investigated the landscapes of histone modifications surrounding retrocopies in these six human cell lines and compared them to those surrounding TAD boundaries.We found that the genomic regions surrounding the colocalized retrocopies rather than the noncolocalized are enriched for active histone markers and CTCF-binding sites in human cell lines,which is similar to the epigenomic landscapes of TAD boundaries,suggesting a potential contribution of retrocopies to maintaining and/or reshaping TADs.The significantly smaller distances between retrocopies and TAD boundaries in both humans and mice could be the result of the retrocopy-mediated formation of new TAD boundaries close to the insertion site or due to the preferred insertion of retrocopies into particular genomic regions near the existing TAD boundaries,or both.To clarify these possibilities,this study selected 967 and 992 retrocopies from human and mouse,respectively,and then computed the distances from both these retrocopy loci and their syntenic regions where no retrocopy is found to the nearest TAD boundaries.Reciprocally comparing the distances from the retrocopy loci and the corresponding syntenic regions to the nearest TAD boundaries in humans and mice showed that the retrocopy-mediated formation of a new TAD boundary may provide a mechanism for such phenomena.Overall,this study provides evidence for retrocopies as important players in the evolution of the higher-order genome architecture.