The functional role of Transposable Elements in the mammalian genome

During recent years, thanks to remarkable technical improvements in the fields of DNA and RNA sequencing, a growing interest in the non-coding part of the genome has prompted researchers to concentrate their efforts in studying Transposable Elements (TEs), repetitive sequences with different possible evolutionary origins, that can move along the genome. Although non-coding DNA has been referred to as “junk DNA” for decades, and Transposable Elements themselves are considered “selfish”, possibly deleterious elements, a steadily growing amount of data suggests that this is not always the case. Multiple studies have linked transposons to tissue-specific differential gene expression, variable chromatin looping and genome compartmentalization. Dry and wet lab work shows that mouse embryonic and extraembryonic stem cells seem to have exapted LTR TE families as enhancers. As a result of a bioinformatic analysis of epigenomic and transcriptomic data, a large number of TEs appear to have an important role in establishing tissue-specific gene expression programmes. Targeted genome editing of individual TEs confirms the presence of regulatory interactions between TE-derived enhancers and tissue-specific promoters. A genome-wide inactivation of RLTR13D6 elements via CRISPR interference in ESCs suggests that only a minority of all known TE families plays a significant role in gene regulation. TE amplification has been linked to chromatin looping variability across different cell types in mouse and human. The 3D genome conformation seems to have been influenced by multiple transpositions of mobile elements containing CTCF binding sites. In fact, numerous CTCF binding sites fall within TE sequences, and transposition seems to be an ideal mechanism for CTCF binding sites expansion, thus impacting chromatin loops formation. TE-derived CTCF binding sites are shown to be subject to different levels of selective pressure in human and mouse, leading to low conservation of chromatin loop structure, that in turn impacts gene expression regulation. Genome compartmentalization appears to be influenced by TEs as well. Retrotransposons belonging to the L1 and B1/Alu classes in mouse and human delimit the genome into large scale domains, following a homotypic clustering of said sequences. FISH techniques show intense accumulation of L1 elements along the nuclear and nucleolar peripheries, whereas B1/Alu elements cluster within the nuclear interior, following a spatial segregation mechanism that occurs dynamically during the cell cycle. L1 and B1/Alu transcripts appear to be involved, since the depletion of L1 transcripts in ESCs weakens homotypic contacts and damages the nuclear segregation of L1- and B1-rich chromosomal regions.