Transposable Elements Co-Option in Genome Evolution and Gene Regulation.

The genome is no longer deemed as a fixed and inert item but rather as a moldable matter that is continuously evolving and adapting. Within this frame, Transposable Elements (TEs), ubiquitous, mobile, repetitive elements, are considered an alive portion of the genomes to date, whose functions, although long considered "dark", are now coming to light. Here we will review that, besides the detrimental effects that TE mobilization can induce, TEs have shaped genomes in their current form, promoting genome sizing, genomic rearrangements and shuffling of DNA sequences. Although TEs are mostly represented in the genomes by evolutionarily old, short, degenerated, and sedentary fossils, they have been thoroughly co-opted by the hosts as a prolific and original source of regulatory instruments for the control of gene transcription and genome organization in the nuclear space. For these reasons, the deregulation of TE expression and/or activity is implicated in the onset and progression of several diseases. It is likely that we have just revealed the outermost layers of TE functions. Further studies on this portion of the genome are required to unlock novel regulatory functions that could also be exploited for diagnostic and therapeutic approaches.

LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion.

How gene expression is controlled to preserve human T cell quiescence is poorly understood. Here we show that non-canonical splicing variants containing long interspersed nuclear element 1 (LINE1) enforce naive CD4+ T cell quiescence. LINE1-containing transcripts are derived from CD4+ T cell-specific genes upregulated during T cell activation. In naive CD4+ T cells, LINE1-containing transcripts are regulated by the transcription factor IRF4 and kept at chromatin by nucleolin; these transcripts act in cis, hampering levels of histone 3 (H3) lysine 36 trimethyl (H3K36me3) and stalling gene expression. T cell activation induces LINE1-containing transcript downregulation by the splicing suppressor PTBP1 and promotes expression of the corresponding protein-coding genes by the elongating factor GTF2F1 through mTORC1. Dysfunctional T cells, exhausted in vitro or tumor-infiltrating lymphocytes (TILs), accumulate LINE1-containing transcripts at chromatin. Remarkably, depletion of LINE1-containing transcripts restores TIL effector function. Our study identifies a role for LINE1 elements in maintaining T cell quiescence and suggests that an abundance of LINE1-containing transcripts is critical for T cell effector function and exhaustion.