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Study on Functions of Histone Variant H2A.Z for the Maintenance of Heterochromatin Integrity
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Title: | Study on Functions of Histone Variant H2A.Z for the Maintenance of Heterochromatin Integrity |
Other Titles: | ヘテロクロマチンにおけるヒストンバリアントH2A.Zの機能に関する研究 |
Authors: | Tsukii, Kazuki1 Browse this author |
Authors(alt): | 月井, 一輝1 |
Issue Date: | 24-Mar-2022 |
Publisher: | Hokkaido University |
Abstract: | Heterochromatin, a silent chromatin is involved in many biological processes, such
as gene silencing, development, chromosome segregation, and genome integrity.
Post translational modifications of histone tails are crucial for heterochromatin
formation. Methylation of histone H3 at Ly9 (H3K9me) is a well conserved
heterochromatic modification. For the formation and maintenance of
heterochromatin, RNAi-dependent and -independent pathways redundantly
functions and recruits H3K9 methyltransferase Clr4 to heterochromatic region. HP1
recognizes H3K9me and forms highly condensed chromatin structure. HP1 recruits
not only silencing factors but also anti-silencing factor Epe1, a H3K9me
demethylase, to heterochromatic regions, suggesting that the competition between
silencing factors and anti-silencing factors is important for proper maintenance of
heterochromatin. As well as histone modifications, histone variants also play
important roles. Especially, H2A.Z is one of the most evolutionally conserved
histone H2A variant. H2A.Z has been implicated in many biological processes,
including gene regulation, mammalian development, DNA replication, and stress
response. In particular, the function of H2A.Z in euchromatic gene regulation is well
studied. H2A.Z is highly enriched at gene promoter and is required for the proper
transcription. However, its function and deposition mechanism in heterochromatin
is still unclear. Here, I show that H2A.Z plays multiple roles in fission yeast
heterochromatin. In fission yeast, H2A.Z is loaded into nucleosomes at TSS of
euchromatic gene by the H2A.Z loader, SWR complex. While a small amount of
H2A.Z localizes at pericentromeric heterochromatin compared to euchromatic gene
promoter, loss of H3K9me induces the accumulation of H2A.Z, which is dependent
on the SWR complex. The accumulated H2A.Z suppresses heterochromatic non coding RNA transcription. This transcriptional repression activity requires the N terminal tail of H2A.Z, which is involved in the regulation of euchromatic gene transcription. Additionally, RNAi defective cells, in which a substantial amount of H3K9me is retained by RNAi-independent heterochromatin assembly, also
accumulate H2A.Z at pericentromeric heterochromatin. The additional loss of
H2A.Z in these cells abolishes H3K9me. Moreover, loss of H2A.Z in RNAi
defective cells decreased H3K9me at the mat locus heterochromatin and
subtelomere heterochromatin, where RNAi is dispensable. However, H2A.Z is not
required for the maintenance of artificially formed ectopic heterochromatin which is
maintained by RNAi-independent mechanism in the absence of Epe1, suggesting the
indirect effects of H2A.Z for RNAi-independent heterochromatin assembly. As
Epe1, an eraser of H3K9me is responsible for the decrease of H3K9me in RNAi
mutants, loss of Epe1 restored the H3K9me in RNAi and H2A.Z double deletion
mutants. These results suggest that H2A.Z facilitates RNAi-independent
heterochromatin assembly by antagonizing the demethylation activity of Epe1.
Furthermore, loss of H2A.Z caused silencing defects at subtelomeric
heterochromatin without affecting H3K9me. Since Epe1 also has a transcription
activation domain at N-terminus, overexpression of Epe1 results in transcriptional
activation at pericentromere without affecting H3K9me. Loss of H2A.Z in Epe1-
overexpressig cells synergistically increases the transcription, and the subtelomeric
silencing defect in H2A.Z deletion mutant is suppressed by loss of Epe1. These
results suggests that H2A.Z suppresses Epe1-mediated transcriptional activation,
which is required for subtelomeric gene repression. Taken together, this study
provides novel evidence that H2A.Z plays diverse roles in chromatin silencing. |
Conffering University: | 北海道大学 |
Degree Report Number: | 甲第14906号 |
Degree Level: | 博士 |
Degree Discipline: | 理学 |
Examination Committee Members: | (主査) 教授 坂口 和靖, 特任教授 髙木 睦, 教授 髙岡 晃教, 教授 村上 洋太 |
Degree Affiliation: | 総合化学院(総合化学専攻) |
Type: | theses (doctoral) |
URI: | http://hdl.handle.net/2115/85255 |
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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