The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells

ABSTRACT

While epigenetic mechanisms such as DNA methylation and histone modification are known to be important for gene suppression, relatively little is still understood about the interplay between these systems. The UHRF1 protein can interact with both DNA methylation and repressive chromatin marks, but its primary function in humans has been unclear. To determine what that was, we first established stable UHRF1 knockdowns (KD) in normal, immortalized human fibroblasts using targeting shRNA, since CRISPR knockouts (KO) were lethal. Although these showed a loss of DNA methylation across the whole genome, transcriptional changes were dominated by the activation of genes involved in innate immune signalling, consistent with the presence of viral RNA from retrotransposable elements (REs). We confirmed using mechanistic approaches that 1) REs were demethylated and transcriptionally activated; 2) this was accompanied by activation of interferons and interferon-stimulated genes and 3) the pathway was conserved across other adult cell types. Restoring UHRF1 in either transient or stable KD systems could abrogate RE reactivation and the interferon response. Notably, UHRF1 itself could also re-impose RE suppression independent of DNA methylation, but not if the protein contained point mutations affecting histone 3 with trimethylated lysine 9 (H3K9me3) binding. Our results therefore show for the first time that UHRF1 can act as a key regulator of retrotransposon silencing independent of DNA methylation.

KEYWORDS:

• Epigenetics
• DNA methylation
• UHRF1
• Retrotransposons
• Virus

Acknowledgments

The work reported was supported by a grant from the Medical Research Council to CPW (MR/J007773/1), a Newton Mobility Grant from the Royal Society to CPW and GLX (IE160973) and grants from the National Institutes of Health (CA181343 and GM124736) to SBR.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

All data have been uploaded to GEO (ncbi.nlm.nih.gov/geo) as GSE128411. All materials and cell lines will be made available from the corresponding author, CPW, upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2023.2216005.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The work was supported by the Medical Research Council [MR/J007773/1]; National Institutes of Health [CA181343]; National Institutes of Health [GM124736]; Royal Society [IE160973]