Posttranscriptional regulation of human endogenous retroviruses by RNA-binding motif protein 4, RBM4

Abstract

The human genome encodes for over 1,500 RNA-binding proteins (RBPs), which coordinate regulatory events on RNA transcripts. Most studies of RBPs have concentrated on their action on host protein-encoding mRNAs, which constitute a minority of the transcriptome. A widely neglected subset of our transcriptome derives from integrated retroviral elements, termed endogenous retroviruses (ERVs), that comprise ∼8% of the human genome. Some ERVs have been shown to be transcribed under physiological and pathological conditions, suggesting that sophisticated regulatory mechanisms to coordinate and prevent their ectopic expression exist. However, it is unknown how broadly RBPs and ERV transcripts directly interact to provide a posttranscriptional layer of regulation. Here, we implemented a computational pipeline to determine the correlation of expression between individual RBPs and ERVs from single-cell or bulk RNA-sequencing data. One of our top candidates for an RBP negatively regulating ERV expression was RNA-binding motif protein 4 (RBM4). We used photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation to demonstrate that RBM4 indeed bound ERV transcripts at CGG consensus elements. Loss of RBM4 resulted in an elevated transcript level of bound ERVs of the HERV-K and -H families, as well as increased expression of HERV-K envelope protein. We pinpointed RBM4 regulation of HERV-K to a CGG-containing element that is conserved in the LTRs of HERV-K-10, -K-11, and -K-20, and validated the functionality of this site using reporter assays. In summary, we systematically identified RBPs that may regulate ERV function and demonstrate a role for RBM4 in controlling ERV expression.

Ancient Adversary – HERV-K (HML-2) in Cancer

“…RNA-binding motif protein 4 (RBM4) was identified to inversely correlate with HERV expression and shown to bind HML-2 RNA at CGG consensus elements. RBM4 knockout led to HML-2 transcript upregulation and increased Env protein expression in the chronic myelogenous leukaemia (CML) HAP1 cell line ( 47 ). RMB4 has been suggested as a tumour suppressor and its reduced expression is associated with poor overall survival in lung, breast, ovarian and gastric cancers ( 48 , 49 ).…”

Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease

“…In addition, the inhibitory activity of KAP1-associated repressive chromatin factors, such as the HDAC1 of the NuRD complex [ 88 , 89 ], is enhanced by methylation-dependent O-linked glycosylation, a PTM introduced by the O-linked β- N -acetylglucosamine transferase (OGT) [ 90 ] ( Figure 1 , number 1). On the other hand, HERVs can also be post-transcriptionally regulated by RNA-binding proteins, such as the RNA-Binding Motif Protein 4 (RBM4) [ 91 ]. RBM4 regulates HERV-K (HML-2) and the HERV-H transcript levels by binding at CGG consensus elements present on 5′ and 3′ LTRs.…”

Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease

“…In addition, the inhibitory activity of KAP1-associated repressive chromatin factors, such as the HDAC1 of the NuRD complex [67,68], is enhanced by methylation-dependent Olinked glycosylation, a PTM introduced by the O-linked β-N-acetylglucosamine transferase (OGT) [69] (Figure 1, number 1). HERVs can also be post-transcriptionally regulated by RNA binding proteins, such as the RNA-Binding Motif Protein 4 (RBM4) [70]. RBM4 regulates HERV-K (HML-2) and HERV-H transcript levels by binding at CGG consensus elements present on 5' and 3' LTRs.…”