Long interspersed nuclear element-1 (LINE-1, L1) shows high transcriptional activity in human pluripotent stem cells (PSCs). Here, we showed that pluripotency-associated transcription factors (TFs) such as POU5F1 (OCT4), SOX2, KLF4, NANOG, and MYC bind to the 5' untranslated region of full-length L1 copies of young subfamilies (L1HS, L1PA2, L1PA3), with their respective consensus sequences containing their binding motifs. These sites display features of open chromatin, H3K4me3 enrichment, and ATAC-seq signals, suggesting potential transcriptional activation. Notably, knockdown of POU5F1 led to increased L1 expression in independent experiments, suggesting that POU5F1 restricts L1 activity in PSCs. Similar trends were observed for SOX2 and NANOG, although supporting mRNA-seq datasets were limited. ChIP-seq analyses revealed binding of POU5F1, SOX2, NANOG, KLF4, and MYC to the 5' UTR of younger L1 subfamilies. Motif analysis revealed that binding sequences for these TFs are also conserved in older L1 subfamilies, suggesting a role for these TF binding in host fitness and/or L1 amplification. Together, our findings support a model in which pluripotency-associated TFs such as POU5F1 preferentially bind to transcriptionally competent L1 loci and modulate L1 expression in human PSCs, although the extent of their regulatory roles may differ among the TFs.
Suzuki et al. (2026) studied this question.