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bioRxiv · 10.1101/2022.11.24.517673

Mouse HP1γ regulates TRF1 expression and telomere stability

Stylianakis, E.·Festenstein, R.·Vannier, J.-B.
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Abstract

AimsTElomeric Repeat-containing RNA are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of Heterochromatin Protein 1 (HP1), a protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1{gamma} is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1{gamma} function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1{gamma} on the transcription of telomere factors and molecules that can affect telomere maintenance. Main methodsWe investigated the telomere function of HP1{gamma} by using deficient mouse embryonic fibroblasts (MEFs) deriving from 13.5 embryonic day embryos compared to their litter mate controls. We used gene expression analysis of HP1{gamma} deficient MEFs and validated the molecular and mechanistic consequences of HP1{gamma} loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA Immunoprecipitation (DRIP). Key findingsLoss of HP1{gamma} in primary MEFs leads to a downregulation of various telomere and telomere-accessory transcripts, including shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage ({gamma}H2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. SignificanceOur results suggest an important transcriptional control by mouse HP1{gamma} of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

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Stylianakis, E., Festenstein, R., Vannier, J.-B.. 2022-11-24. Mouse HP1γ regulates TRF1 expression and telomere stability. https://doi.org/10.1101/2022.11.24.517673

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