Abstract
Heterochromatin, a highly compact chromatin state characterized by histone H3K9 methylation and HP1 protein binding, silences the underlying DNA and influences the expression of neighboring genes. However, the mechanisms that regulate heterochromatin spreading are not well understood. In this study, we show that the conserved Mst2 histone acetyltransferase complex in fission yeast regulates histone turnover at heterochromatin regions to control heterochromatin spreading and prevents ectopic heterochromatin assembly. The combined loss of Mst2 and the JmjC domain protein Epe1 results in uncontrolled heterochromatin spreading and massive ectopic heterochromatin, leading to severe growth defects due to the inactivation of essential genes. Interestingly, these cells quickly recover by accumulating heterochromatin at genes essential for heterochromatin assembly, leading to their reduced expression to restrain heterochromatin spreading. Our studies discover redundant pathways that control heterochromatin spreading and prevent ectopic heterochromatin assembly and reveal a fast epigenetic adaptation response to changes in heterochromatin landscape.
Highlights
Eukaryotic genomic DNA is folded with histones and non-histone proteins in the form of chromatin, which regulates every aspect of DNA metabolism, including transcription, replication, recombination, and DNA damage repair
We found that pericentric dh repeat was associated with lower amounts of H3-Flag in wild-type cells compared with RNA interference (RNAi) mutant dcr1Δ (Figure 1C), suggesting that histone turnover rates increase when heterochromatin is compromised
We found that mst2Δ epe1Δ dcr1Δ cells quickly recovered and H3K9me2 levels were similar at the clr4+ locus in mst2Δ epe1Δ* and mst2Δ epe1Δ dcr1Δ* cells, suggesting that RNAi is not required for heterochromatin assembly at clr4+, even though clr4+ is in a convergent orientation with meu6+ (Figure 5—figure supplement 1)
Summary
Eukaryotic genomic DNA is folded with histones and non-histone proteins in the form of chromatin, which regulates every aspect of DNA metabolism, including transcription, replication, recombination, and DNA damage repair. Chromatin is classified into euchromatin, which is gene rich and actively transcribed, and heterochromatin, which is gene poor and highly compacted (Grewal and Jia, 2007). Heterochromatin preferentially forms at repetitive DNA elements in order to limit transcription and recombination at these regions to maintain genome integrity. It forms at developmentally regulated genes to regulate their expression in response to developmental cues and external stimuli. Heterochromatin tends to spread into neighboring regions, leading to the inactivation of genes in a sequence-independent manner (Talbert and Henikoff, 2006; Wang et al, 2014). The sites of heterochromatin formation and extent of heterochromatin spreading need to be tightly controlled to prevent improper gene silencing, and misregulation of heterochromatin assembly has been linked to many human diseases, especially various types of cancers (Geutjes et al, 2012)
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