Transposable element sequence fragments incorporated into coding and noncoding transcripts modulate the transcriptome of human pluripotent stem cells

Abstract

Transposable elements (TEs) occupy nearly 40% of mammalian genomes and, whilst most are fragmentary and no longer capable of transposition, they can nevertheless contribute to cell function. TEs within genes transcribed by RNA polymerase II can be copied as parts of primary transcripts; however, their full contribution to mature transcript sequences remains unresolved. Here, using long and short read (LR and SR) RNA sequencing data, we show that 26% of coding and 65% of noncoding transcripts in human pluripotent stem cells (hPSCs) contain TE-derived sequences. Different TE families are incorporated into RNAs in unique patterns, with consequences to transcript structure and function. The presence of TE sequences within a transcript is correlated with TE-type specific changes in its subcellular distribution, alterations in steady-state levels and half-life, and differential association with RNA Binding Proteins (RBPs). We identify hPSC-specific incorporation of endogenous retroviruses (ERVs) and LINE:L1 into protein-coding mRNAs, which generate TE sequence-derived peptides. Finally, single cell RNA-seq reveals that hPSCs express ERV-containing transcripts, whilst differentiating subpopulations lack ERVs and express SINE and LINE-containing transcripts. Overall, our comprehensive analysis demonstrates that the incorporation of TE sequences into the RNAs of hPSCs is more widespread and has a greater impact than previously appreciated.

Expression of Human Endogenous Retroviruses in the Human Thymus Along T Cell Development

“…We show here that the expression of HERV-K, -W, and -R decrease along T cell development in the human thymus. The highest levels in the early stages are in line with the high levels previously described in hematopoietic progenitors (8,9), and may be in part related to the high proliferative rate of immature thymocytes (26). HERV expression in thymocytes is particularly important in the human context given the possible contribute of T-T interactions to the T cell selection through the expression of MHC class II (4,26).…”

“…Therefore, human endogenous retroviruses (HERVs), which represent close to 8% of the human genome, are likely to be important players in the thymus. HERVs are known to be expressed in stem cells, including hematopoietic stem cells, and have been shown to play a role in lineage commitment (8,9). Moreover, several HERV families have been shown to be expressed in the human thymus (10)(11)(12)(13)(14).…”

“…Recent data from several cell types and tissues have also been highlighting host restriction factors that limit HERV expression (9), and the interplay with other viruses, including HIV and SARS-CoV-2 (7,(18)(19)(20)(21)(22). It is likely that the interplay between HERV expression and the activation of the cell-intrinsic pathways that detect cytoplasmic DNA and/or RNA may play a role in the response to viral infections, as well as in the human thymus, including possible modulation during cell selection (10).…”

Active endogenous retroviral elements in human pluripotent stem cells play a role in regulating host gene expression

“…Our data indicate that most of the HERVK transcripts are located in the nucleus, and combined with histone modification, YY1 and POLII enrichment ( Supplementary Table S2 and S3 ), indicating a possibility that HERVK may act as eRNA ( 76 ). Interestingly, a couple of previous studies reported that the viral protein encoded by HERVK could be detected in pluripotent cells ( 61 , 77 ), suggesting a potential diverse role of HERVK. Through motif enrichment analysis, we found that LTR5_Hs/LTR5 enriched transcription factors, such as KLF4/5 and TFAP2C, highly related to early embryo status, so we further surveyed the early embryo cells and found that LTR5_Hs/LTR5 is more active in naïve ESCs and ffEPSCs (Figure 5D ).…”

Transposable Elements in Pluripotent Stem Cells and Human Disease

“…Syncytin-1 is also high in the brains of schizophrenia patients, this correlates with the expression of the inflammation marker CRP ( Wang et al, 2018 ). In addition to these examples, peptides derived from TE sequences have been detected in several cell types ( Grow et al, 2015 ; Li et al, 2015 ; Babarinde et al, 2021 ) ( Figure 1B ), although their function (if any) remains unclear.…”