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A histone H3 methyltransferase controls epigenetic events required for meiotic prophase

Abstract

Epigenetic modifications of histones regulate gene expression and chromatin structure1,2. Here we show that Meisetz (meiosis-induced factor containing a PR/SET domain and zinc-finger motif) is a histone methyltransferase that is important for the progression of early meiotic prophase. Meisetz transcripts are detected only in germ cells entering meiotic prophase in female fetal gonads and in postnatal testis. Notably, Meisetz has catalytic activity for trimethylation, but not mono- or dimethylation, of lysine 4 of histone H3, and a transactivation activity that depends on its methylation activity. Mice in which the Meisetz gene is disrupted show sterility in both sexes due to severe impairment of the double-stranded break repair pathway, deficient pairing of homologous chromosomes and impaired sex body formation. In Meisetz-deficient testis, trimethylation of lysine 4 of histone H3 is attenuated and meiotic gene transcription is altered. These findings indicate that meiosis-specific epigenetic events in mammals are crucial for proper meiotic progression.

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Figure 1: Molecular structure and expression of the Meisetz gene.
Figure 2: Meisetz protein catalyses H3K4 trimethylation and activates transcription through its methylation activity.
Figure 3: Impairment of meiotic progression in Meisetz -/- mice.
Figure 4: Downregulation of H3K4 trimethylation and meiotic gene expression in Meisetz -/- testis.

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Acknowledgements

We thank N. Nakatsuji and S. Chuma for anti-SCP3 antibody; Y. Nishimune for TRA369 antibody; T. Noce for anti-mVASA antibody; H. Kai and Y. Seki for pcDNA3GAL4DBD; J. Miyazaki for pCAGGS; M. Saitou for confocal microscopy; and M. Tachibana and Y. Shinkai for GST-fused histone H3 expression vectors. This work was supported in part by CREST of JST (Japan Science and Technology Agency), and by grants-in-aid and Special Coordinating Funds for Promoting Science and Technology from the Ministry of Education, Science, Sports and Culture of Japan.

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Correspondence to Yasuhisa Matsui.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

A list of genes isolated by the subtraction analysis. (PDF 599 kb)

Supplementary Figure 2

Nucleotide and amino acid sequences of Meisetz. (PDF 4922 kb)

Supplementary Figure 3

H3K4 trimethylation activity of Meisetz. (PDF 62 kb)

Supplementary Figure 4

Targeted disruption of Meisetz. (PDF 92 kb)

Supplementary Figure 5

Sequence alignment of GHKL motif in the 4932411A10Rik gene. (PDF 635 kb)

Supplementary Legends

Legends to accompany the above Supplementary Figures. (DOC 31 kb)

Supplementary Methods

This file contains Supplementary Method and additional references. (DOC 48 kb)

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Hayashi, K., Yoshida, K. & Matsui, Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature 438, 374–378 (2005). https://doi.org/10.1038/nature04112

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  • DOI: https://doi.org/10.1038/nature04112

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