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Study on Functions of the Heterochromatin Factor Epe1 to Regulate Epigenetic Diversification

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Title: Study on Functions of the Heterochromatin Factor Epe1 to Regulate Epigenetic Diversification
Other Titles: エピジェネティックな多様化を制御するヘテロクロマチン因子Epe1 の機能に関する研究
Authors: 反田, 真登 Browse this author
Issue Date: 25-Sep-2019
Abstract: Post-translational modifications of histones are involved in various cellular events. Methylation of histone H3 at lysine 9 (H3K9me) is a conserved marker for formation of heterochromatin, a transcriptionally silent chromatin structure. Heterochromatin formation is limited to specific genomic loci, but the mechanism for regulating heterochromatin distribution is not fully understood. The fission yeast JmjC domain-containing protein Epe1 localizes to heterochromatin mainly through its physical interaction with Swi6, a homologue of heterochromatin protein 1 (HP1), and directs JmjC-mediated demethylation of H3K9me in vivo. However, the physiological role of Epe1 in the control of the genome-wide heterochromatin landscape is unknown. Here, I found that loss of epe1 (epe1Δ) induced a red-white variegated phenotype in a red-pigment accumulation background in contrast to the wild-type strain, which generated uniform red colonies. Analysis of isolated red and white colonies revealed that white colony formation was due to silencing of genes involved in red-pigment accumulation by stochastic ectopic heterochromatin formation. In addition, genome-wide analysis of red- and white-isolated clones revealed that epe1Δ resulted in a heterogeneous heterochromatin distribution among clones. These results suggest that multiple potential H3K9me deposition sites exist in the genome and that Epe1 has a genome-wide function to suppress stochastic formation of ectopic heterochromatin. I found that Epe1 had an N-terminal domain distinct from its JmjC domain, which activated transcription in both fission and budding yeasts. Deletion of the N-terminal transcriptional activation (NTA) domain induced ectopic heterochromatin-mediated red-white variegation with lower pink- and white-colony ratio than epe1Δ, suggesting that the NTA domain contributes to suppression of ectopic heterochromatin formation in a JmjC-independent mechanism. I introduced a single copy of epe1 into epe1Δ clones harboring ectopic heterochromatin, and found that Epe1 could reduce H3K9me from ectopic heterochromatin. Epe1H297A, a canonical JmjC mutant, suppressed red-white variegation, but entirely failed to remove already-established ectopic heterochromatin, indicating that JmjC domain is not required for suppression of ectopic heterochromatin establishment but essential for removal of established ectopic heterochromatin. I found that some of the ectopic heterochromatin persisted after introduction of a single copy of epe1. This persistence was due to a latent H3K9me source embedded in ectopic 7 heterochromatin. The latent H3K9me source did not initiate deposition of H3K9me in the presence of Epe1, while contributing to maintenance of established heterochromatin. Overexpression of Epe1 depleted the persistent ectopic heterochromatin. These results suggest that the efficiency of Epe1-mediated removal of established ectopic heterochromatin was controlled in a dose-dependent manner and that single copy Epe1 contributed to producing an epigenetic difference. These results suggested that Epe1 prevented stochastic de novo deposition of ectopic H3K9me in an NTA-dependent but JmjC-independent manner, while promoting JmjC domain-mediated removal of H3K9me from established ectopic heterochromatin. Taken together, these findings suggest that Epe1 not only limits the distribution of heterochromatin but also controls the balance between suppression and retention of heterochromatin-mediated epigenetic diversification.
Conffering University: 北海道大学
Degree Report Number: 甲第13805号
Degree Level: 博士
Degree Discipline: 理学
Examination Committee Members: (主査) 教授 坂口 和靖, 教授 村上 洋太, 教授 藤田 恭之, 教授 松本 謙一郎, 教授 髙岡 晃教
Degree Affiliation: 総合化学院(総合化学専攻)
Type: theses (doctoral)
Appears in Collections:課程博士 (Doctorate by way of Advanced Course) > 総合化学院(Graduate School of Chemical Sciences and Engineering)
学位論文 (Theses) > 博士 (理学)

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