Abstract
Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing.
Highlights
Chromatin structure alterations help to establish gene silencing, which in part explains heritable gene expression patterns
Changes in epigenetic silencing are linked with different stages of tumor formation and progression
By applying a genome-wide silencing screening approach, we identified the conserved subunits of the mismatch repair (MMR) machinery (Pms1, Mlh1 and Msh2) as new components of the epigenetic silencing regulation machinery in yeast
Summary
Chromatin structure alterations help to establish gene silencing, which in part explains heritable gene expression patterns. Similar (but less robust) silencing occurs at the telomeres, Sir and Sir were found to associate with RAP1 at the telomeres, and Rap and yKu70 proteins recruit the Sir, Sir andSir complex to establish the chromatin-mediated gene repression at yeast telomeric regions [8, 9]. Silencing at these loci requires the recruitment of Sir to the correct genomic locations [10,11,12]. The mating-type cassette silencing phenotype of SIR1 mutants is a classical example of epigenetically inherited gene silencing, and this kind of silencing phenotype can be used as a readout for an SGA-based screening (which acquires strain’s proper mating ability) for identifying new genes affecting this process
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
