Mouse HP1? regulates TRF1 expression and telomere stability

Aims: Telomeric repeat-containing RNAs 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 members of the heterochromatin protein 1 (HP1) 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 methods: We investigated the telomere function of HP1 & gamma; by using HP1 & gamma; deficient mouse embryonic fibroblasts (MEFs). 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 findings: Loss of HP1 & gamma; in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the 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.Significance: Our 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.