New insights into the functional role of retrotransposon dynamics in mammalian somatic cells

Abstract

Retrotransposons are genetic elements present across all eukaryotic genomes. While their role in evolution is considered as a potentially beneficial natural source of genetic variation, their activity is classically considered detrimental due to their potentially harmful effects on genome stability. However, studies are increasingly shedding light on the regulatory function and beneficial role of somatic retroelement reactivation in non-pathological contexts. Here, we review recent findings unveiling the regulatory potential of retrotransposons, including their role in noncoding RNA transcription, as modulators of mammalian transcriptional and epigenome landscapes. We also discuss technical challenges in deciphering the multifaceted activity of retrotransposable elements, highlighting an unforeseen central role of this neglected portion of the genome both in early development and in adult life.

Keywords: Cell identity; Development; Gene expression; Repetitive RNA; Retrotransposon.

Fig. 1

Retrotransposons as cis-regulatory elements. a Example of transposable elements functioning as alternative promoters in 2C-like ES cells. Embryonic stem (ES) cells, the pluripotent cells derived from the inner cell mass of the blastocyst, are able to differentiate into all embryo tissues. However, a subpopulation of ES cells can be distinguished for its ability to differentiate into both embryo and extra-embryonic tissues (totipotency). These cells recapitulate the same transcriptional state of totipotent 2 cells, where MERV elements are transcriptionally active and work as alternative promoters for two-cell stage specific genes. b Example of transposable elements functioning as enhancers. ERV and L1 enriched enhancers in cranial neural crest cells (CNCC) affect the expression of genes involved in craniofacial development. Divergent enhancers between human and chimp contribute to species-specific facial phenotypes. The differential activity of these species-biased enhancers also affects intra-human facial variation

Fig. 2

Retrotransposons as non-coding RNA. a Example of TE-derived RNA functioning as non-coding RNA during early development. In pre-implantation embryos L1 are transcriptionally active. L1 RNA association to chromatin led to global chromatin relaxation. L1 RNA associates with KAP1 and Nucleolin at rDNA loci inducing their transcription, while repressing DUX and 2C-specific genes to proceed with the development. b Example of TE-derived RNA functioning as non-coding RNA in stress response. In resting cells SINE B2 RNA associates with stress response genes inhibiting RNA Pol II elongation. When cells are stressed the binding of EZH2 to stress loci enhances the self-cleavage activity of the B2 ribozyme, thus releasing Pol II and allowing transcription of stress response loci

Fig. 3

Retrotransposons as 3D genome architecture orchestrators. a L1 RNA associates to L1 DNA and mediates the sequestration of L1-enriched genes in the inactive compartment (B), at the nuclear periphery, for silencing. NAD Nucleolar-Associated Domain, LAD Lamina-Associated Domain. Active genes are barcoded by SINEs and localized in the nuclear interior (compartment A) where they are actively transcribed. SINE elements are enriched for CTCF binding sites, represent TADs (Topologically Associated Domains) boundaries and contribute to chromatin looping. b In hESC, transcriptionally active HERV-H forms pluripotent specific TAD boundaries which weaken during differentiation to cardiomyocytes. Transcription at HERV-H loci is crucial for maintaining chromatin looping at HERV-H-dependent TADs