Some pesky Polycomb-target genes know too much about genome-wide goings-on, and while these nervous sections of DNA might keep silent for now, how can we ensure that our cells maintain this code of silence? It turns out that human cells, just as in yeast, possess an enforcer that mercilessly chops up RNA messages produced from silenced, heterochromatin-resident genes to keep things on the lowdown – the rixosome!
Silencing developmental genes and maintaining cell fate requires Polycomb repressive complex 1 and 2 (PRC1 and PRC2)-mediated heterochromatin formation; meanwhile, studies in yeast have also provided evidence for the role of an RNA-degradation complex known as the rixosome or RIX1 complex, which has a role in heterochromatin establishment, maintenance, and epigenetic inheritance. A study from the serene surroundings of the Danesh Moazed lab (Harvard, USA) explored whether human rixosomes play similar roles in heterochromatin regulation/gene silencing and discovered evidence that PRCs recruit rixosomes to Polycomb-target genes to induce RNA degradation (keeping tattle-tale genes quiet!) and support heterochromatin maintenance.
Let’s hear from Zhou and colleagues on how rixosomes keep Polycomb-target genes silent by taking-out nascent RNAs:
- Immunoprecipitation assays confirm the physical interaction of PRCs and rixosomes, with purified RING1B (PRC1) directly interacting with the TEX10 rixosome subunit
- ChIP–seq studies reveal the colocalization of rixosome subunits (TEX10 & MDN1) with RING1B (PRC1) and Polycomb-catalyzed histone modifications (H2AK119ub1 & H3K27me3) at gene promoters
- Rixosome-occupied genes also display H3K4me3, suggesting the presence of rixosomes at loci with engaged Pol II, which include bivalent Polycomb domains
- Immunofluorescence shows that EZH2 (PRC2) domains also overlap with rixosome subunits (MDN1 & WDR18)
- Loss of RING1A/B (PRC1) or EZH1/2 (PRC2) abolishes TEX10/MDN1 colocalization at Polycomb-target genes, suggesting that rixosome localization requires PRC subunits
- Rixosome recruitment to target loci requires the specific TEX10-RING1B interaction
- Precision run-on sequencing (PRO-seq) and RNA-seq suggest that rixosomes and PCRs repress the expression of a common set of genes in human cells
- Depletion of rixosome/PRC components prompts the accumulation of paused/elongating Pol II at Polycomb-target genes and increased RNA production, suggesting that recruited rixosomes block transcription
- Silencing of Polycomb-target genes requires the RNA endonuclease/kinase activities of rixosomes and the downstream 5′–3′ exoribonuclease XRN2 (degrades rixosome-generated RNAs), highlighting a requirement for nascent RNA cleavage and transcription termination
This deafening description of rixosome-mediated silencing of Polycomb-target genes suggests an additional layer of gene silencing regulation involving RNA degradation. The authors propose that recruited rixosomes survey PRC-silenced genes for any RNA messages, a sign of weakened Polycomb-mediated repression, and process RNA for degradation.
To find out how rixosomes take out RNAs to keep heterochromatin-resident Polycomb-target genes quiet, see Nature, March 2022.