Transposable Element-Gene Splicing Modulates the Transcriptional Landscape of Human Pluripotent Stem Cells

Abstract

Transposable elements (TEs) occupy nearly 50% of mammalian genomes and are both potential dangers to genome stability and functional genetic elements. TEs can be expressed and exonised as part of a transcript, however, their full contribution to the transcript splicing remains unresolved. Here, guided by long and short read sequencing of RNAs, we show that 26% of coding and 65% of non-coding transcripts of human pluripotent stem cells (hPSCs) contain TEs. Different TE families have unique integration patterns with diverse consequences on RNA expression and function. We identify hPSC-specific splicing of endogenous retroviruses (ERVs) as well as LINE L1 elements into protein coding genes that generate TE-derived peptides. Finally, single cell RNA-seq reveals that proliferating hPSCs are dominated by ERV-containing transcripts, and subpopulations express SINE or LINE-containing transcripts. Overall, we demonstrate that TE splicing modulates the pluripotency transcriptome by enhancing and impairing transcript expression and generating novel transcripts and peptides.

Induced pluripotent stem cells display a distinct set of MHC I-associated peptides shared by human cancers

“…Their MCS was significantly more expressed in cancer samples than the corresponding normal tissues (Figures 2A, 3, S5B, and S5C). These paMAPs had different origins: (1) ZSCAN10, FOXH1, and TAF4, which are transcription factors involved in pluripotency maintenance and embryonic development and are known to promote self-renewal in cancer (Kazantseva et al, 2016;Loizou et al, 2019;Wang et al, 2007Wang et al, , 2019Yu et al, 2009), (2) the oncofetal antigen CLDN6 (Reinhard et al, 2020), and (3) the prostate-cancer associated, ''exonized'' transposable element, PCAT14 (Babarinde et al, 2020;Prensner et al, 2011) (Figure S5A). In addition, two of our paMAPs derived from MAGEA4 (GVYDGREHTV and KVLEHVVRV) and overexpressed in cancer samples (Figure S5B) were immunogenic in previous studies (Duffour et al, 1999;Jia et al, 2010), altogether reinforcing the therapeutic potential of paMAPs.…”