Human pluripotent stem cells (hPSCs), which include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), infinitely self-renew, and can differentiate into any cell type on the human body [1–3]. hESCs are derived from early human embryos and became widely used to study the molecular pathways specific to human embryogenesis [1, 4–8]. Considering the ethical challenge in using embryo-derived cells and the possible immune rejection, hiPSCs are currently more common for regenerative therapies [3, 9–11]. hiPSCs are reprogrammed from a somatic cell line of a patient, genetically modified, and then differentiated to the desired lineage to transplant them back to the patient. hiPSCs are the future of personalized medicine, but not every hiPSC line can differentiate to every given cell type, as a result of cell heterogeneity. To reduce this heterogeneity, a naïve cell state might be a solution [3]. Whereas cultured hPSCs reside in a primed state, the cells of pre-implantation embryos resemble naïve pluripotency [12–16]. By adjusting culture conditions, it is possible to support hPSCs in a naïve state, similar in gene expression signature to early embryos [4, 5, 17–19]. The similarity is reflected as well in transcripts of some of the L1, Alu, and SVA retroelements (REs) [5]. These REs are phylogenetically young and still active human transposons, which might be detrimental for the integrity of the genome [20–27]. Our research group had previously derived the different types of naïve cells, resembling the later stages of pre-implantation development and highly expressing human endogenous retrovirus H (HERVH) [6]. HERVH is a phylogenetically older endogenous retrovirus, which was transposing following New- and Old-World monkey separation [28–30]. Now, HERVH can’t mobilize, but its transcripts were shown to support pluripotency in later stages of human embryogenesis, reprogramming, and in cultured primed hPSCs [6, 7, 31, 32]. Here I show that HERVH controls the transposition of young REs. In HERVH-depleted hESCs, L1 transposition increases, which is measured by two transposition assays. The active L1 elements drive the transposition of non-autonomous REs, resulting in the accumulation of de novo Alus and SVAs integrations, shown by whole-genome sequencing of cells undergoing stable HERVH knock-down. A subgroup of HERVH has the potential to control L1 transposition. These HERVHlin loci contain lin motif, two tandem LIN28A binding sites [33]. HERVHlin is supposedly evolutionary younger than the other HERVH. There are around 100 of HERVHlin sequences in the human, chimp, and gorilla genomes, while less exist in orangutans, and none in other primates. Based on the analysis of the previously published CLIP-seq data [33] and performed RIP-qPCRs, the lin motif allows LIN28A to bind HERVHlin more efficiently than other HERVH transcripts. LIN28A is known to inhibit the maturation of let-7 microRNA [34–37], which in turn controls the transposition of L1 [38]. HERVHlin sponging LIN28A to allow let-7-mediated inhibition of L1 might be the molecular mechanism of HERVH-controlled transposition of young REs. The supporting experiment shows that a let-7 independent L1-ORFeus reporter does not change the transposition activity in HERVH-depleted cells. HERVHlin embedded itself in a previously conservative pluripotency-specific LIN28A-let-7 pathway to protect the genome of hESCs from the mutagenic activity of REs. This is an example of a new evolutionary event where the selfish transposon HERVH evolved to compete with other transposable elements, which could be harmful to the host.
