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Regulation of ectopic heterochromatin-mediated epigenetic diversification by the JmjC family protein Epe1

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Title: Regulation of ectopic heterochromatin-mediated epigenetic diversification by the JmjC family protein Epe1
Authors: Sorida, Masato Browse this author
Hirauchi, Takahiro Browse this author
Ishizaki, Hiroaki Browse this author
Kaito, Wataru Browse this author
Shimada, Atsushi Browse this author
Mori, Chie Browse this author
Chikashige, Yuji Browse this author →KAKEN DB
Hiraoka, Yasushi Browse this author →KAKEN DB
Suzuki, Yutaka Browse this author →KAKEN DB
Ohkawa, Yasuyuki Browse this author →KAKEN DB
Kato, Hiroaki Browse this author →KAKEN DB
Takahata, Shinya Browse this author →KAKEN DB
Murakami, Yota Browse this author →KAKEN DB
Keywords: Heterochromatin
Schizosaccharomyces pombe
DNA transcription
Plasmid construction
Issue Date: Jun-2019
Publisher: PLOS
Journal Title: PLoS Genetics
Volume: 15
Issue: 6
Start Page: e1008129
Publisher DOI: 10.1371/journal.pgen.1008129
Abstract: H3K9 methylation (H3K9me) is a conserved marker of heterochromatin, a transcriptionally silent chromatin structure. Knowledge of the mechanisms for regulating heterochromatin distribution is limited. The fission yeast JmjC domain-containing protein Epe1 localizes to heterochromatin mainly through its interaction with Swi6, a homologue of heterochromatin protein 1 (HP1), and directs JmjC-mediated H3K9me demethylation in vivo. Here, we found that loss of epe1 (epe1 Delta) induced a red-white variegated phenotype in a red-pigment accumulation background that generated uniform red colonies. Analysis of isolated red and white colonies revealed that silencing of genes involved in pigment accumulation by stochastic ectopic heterochromatin formation led to white colony formation. In addition, genome-wide analysis of red- and white-isolated clones revealed that epe1 Delta resulted in a heterogeneous heterochromatin distribution among clones. We found that Epe1 had an N-terminal domain distinct from its JmjC domain, which activated transcription in both fission and budding yeasts. The N-terminal transcriptional activation (NTA) domain was involved in suppression of ectopic heterochromatin-mediated red-white variegation. We introduced a single copy of Epe1 into epe1 Delta clones harboring ectopic heterochromatin, and found that Epe1 could reduce H3K9me from ectopic heterochromatin but some of the heterochromatin persisted. This persistence was due to a latent H3K9me source embedded in ectopic heterochromatin. Epe1H297A, a canonical JmjC mutant, suppressed red-white variegation, but entirely failed to remove already-established ectopic heterochromatin, suggesting that Epe1 prevented stochastic de novo deposition of ectopic H3K9me in an NTA-dependent but JmjC-independent manner, while its JmjC domain mediated removal of H3K9me from established ectopic heterochromatin. Our results suggest that Epe1 not only limits the distribution of heterochromatin but also controls the balance between suppression and retention of heterochromatin-mediated epigenetic diversification. Author summary Suppression of unscheduled epigenetic alterations is important for maintenance of homogeneity among clones, while emergence of epigenetic differences is also important for adaptation or differentiation. The mechanisms that balance both processes warrant further investigation. Epe1, a fission yeast JmjC domain-containing protein, is thought to be an H3K9me demethylase that targets ectopic heterochromatin via its JmjC-dependent demethylation function. Here we found that loss of epe1 induced stochastic ectopic heterochromatin formation genome-wide, suggesting that the fission yeast genome had multiple potential heterochromatin formation sites, which were protected by Epe1. We found that Epe1 prevented deposition of ectopic H3K9me independently of its JmjC-mediated demethylation before heterochromatin establishment. By contrast, Epe1 could attack already-established ectopic heterochromatin via its JmjC domain, but demethylation was not 100% effective, which provided a basis for epigenetic variation. Together, our findings indicate that Epe1 is involved in both maintenance and alteration of heterochromatin distribution, and shed light on the mechanisms controlling individual-specific epigenome profiles.
Type: article
Appears in Collections:理学院・理学研究院 (Graduate School of Science / Faculty of Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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