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

Abstract

Human endogenous retroviruses, also called LTR elements, can be bound by transcription factors and marked by different histone modifications in different biological contexts. Recently, individual LTR or certain subclasses of LTRs such as LTR7/HERVH and LTR5_Hs/HERVK families have been identified as cis-regulatory elements. However, there are still many LTR elements with unknown functions. Here, we dissected the landscape of histone modifications and regulatory map of LTRs by integrating 98 ChIP-seq data in human embryonic stem cells (ESCs), and annotated the active LTRs enriching enhancer/promoter-related histone marks. Notably, we found that MER57E3 functionally acted as proximal regulatory element to activate respective ZNF gene. Additionally, HERVK transcript could mainly function in nucleus to activate the adjacent genes. Since LTR5_Hs/LTR5 was bound by many early embryo-specific transcription factors, we further investigated the expression dynamics in different pluripotent states. LTR5_Hs/LTR5/HERVK exhibited higher expression level in naïve ESCs and extended pluripotent stem cells (EPSCs). Functionally, the LTR5_Hs/LTR5 with high activity could serve as a distal enhancer to regulate the host genes. Ultimately, our study not only provides a comprehensive regulatory map of LTRs in human ESCs, but also explores the regulatory models of MER57E3 and LTR5_Hs/LTR5 in host genome.

Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells

“…7a, 7b ). This observation is consistent with the notion that the LTR7 can act as hESC enhancers to control the expression of distal human genes 43, 79 . By contrast, these human genes regulated by distal LTR7s are less likely to be affected by shRNA-mediated HERV-H knock-down.…”

Sequence Divergence and Retrotransposon Insertion Underlie Interspecific Epigenetic Differences in Primates

“…In the present study, we revealed that LTR5_Hs and LTR5_Pt carry a SOX2 binding motif (nucleotide positions 681–686), in addition to the previously identified POU5F1 motif (positions 692–698) ( Glinsky 2015 ; Grow et al 2015 ), which together form a POU5F1-SOX2 dual binding motif. Consistently, it was recently reported that the ChIP-seq data of both POU5F1 and SOX2 showed a peak in the region encompassing this motif in LTR5_Hs in human iPSCs ( Monde et al 2022 ) and human ESCs ( Zhang et al 2022 ). Owing to the sequence motif, retrotransposed LTR5_Hs and LTR5_Pt copies bind to POU5F1 and SOX2 and gain active histone marks, which underlie the species-specific active chromatin environment and activation of nearby genes in iPSCs.…”

Comprehensive Identification and Characterization of HML-9 Group in Chimpanzee Genome

“…On chromosomes 4, 5, 6, and 7, the actual number of identifications was lower than anticipated (Figure 1C). Notably, HML-9 provirus integration was not detected on chromosomes 1, 2B, 3,9,10,11,12,14,17,18,20,21,22, or X. For solo LTRs elements, the number of HML-9 solo LTRs on chromosomes 2A, 2B, 3, 7, 14, 21, X, and Y was higher than the expected number of integrations.…”