Abstract

Heterochromatinisation of pericentromeres, which in mice consist of arrays of major satellite repeats, are important for centromere formation and maintenance of genome stability. The dysregulation of this process has been linked to genomic stress and various cancers. Here we show in mice that the proteasome binds to major satellite repeats and proteasome inhibition by MG132 results in their transcriptional de-repression; this de-repression is independent of cell-cycle perturbation. The transcriptional activation of major satellite repeats upon proteasome inhibition is accompanied by delocalisation of heterochromatin protein 1 alpha (HP1α) from chromocentres, without detectable change in the levels of histone H3K9me3, H3K4me3, H3K36me3 and H3 acetylation on the major satellite repeats. Moreover, inhibition of the proteasome was found to increase the number of chromocentres per cell, reflecting destabilisation of the chromocentre structures. Our findings suggest that the proteasome plays a role in maintaining heterochromatin integrity of pericentromeres.

Highlights

  • Packaging of DNA into chromatin plays an important role in transcriptional regulation

  • To investigate whether the proteasome might participate in transcriptional silencing of heterochromatin, proteasome binding at pericentromeric and several other endogenous repeats was analysed using Chromatin Immunoprecipitation (ChIP)-seq data previously obtained in mouse 3T3-L1 cells [47]

  • Transcriptional activation of major satellite repeats expression upon proteasome inhibition To assess the role of the proteasome at major satellite repeats, pericentromeric transcription was assessed in NIH3T3 cells treated with a widely used and specific proteasome inhibitor

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Summary

Introduction

Packaging of DNA into chromatin plays an important role in transcriptional regulation. Multiple factors including transcription factors, post-translational histone modifications and DNA methylation are thought to maintain heterochromatin repression [2]. Constitutive heterochromatin predominantly consists of satellite repeats. Heterochromatinisation of pericentromeric repeats is important for centromere formation and maintenance of genome stability [6]. Low levels of pericentromeric satellite repeat transcription have been detected under various physiological conditions, including cell cycle, senescence, development and differentiation [7,8,9,10]. Aberrant overexpression of pericentromeric satellite repeats has been detected in several pathological conditions, including cellular stress [11,12,13], cancer [14,15,16,17] and some genetic disorders [18,19,20]

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