Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation

Atsumi Iida, Toshiro Iwagawa, Yukihiro Baba, Shinya Satoh, Yujin Mochizuki, Hiromitsu Nakauchi, Takahisa Furukawa, Haruhiko Koseki, Akira Murakami, Sumiko Watanabe

Research output: Contribution to journalArticle

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Abstract

The histone modification H3K27me3 regulates transcription negatively, and Jmjd3 and Ezh2 demethylate and methylate H3K27me3 and H3K27, respectively. We demonstrated previously that Jmjd3 plays pivotal roles in the differentiation of subsets of bipolar (BP) cells by regulating H3K27me3 levels at the Bhlhb4 and Vsx1 loci, both of which are transcription factors essential for the maturation of BP cell subsets. In this study, we examined the role of Ezh2 in retinal development using retina-specific Ezh2 conditional knockout mice (Ezh2-CKO). The eyes of the Ezh2-CKO mice were microphthalemic, and the proliferation of retinal cells was diminished postnatally in Ezh2-CKO. Differentiation of all examined retinal subsets was observed with higher proportion of BP cell subsets, which was determined by immunostaining using specific retinal markers. The onsets of Müller glia and rod photoreceptor differentiation were accelerated. The expression of Bhlhb4 was increased in postnatal retinas, which was accompanied by the loss of H3K27me3 modifications at these genetic loci. Decreased expression of proneural genes in postnatal stage was observed. As reported previously in other Ezh2-KO tissues, increased expression of Arf/Ink4a was observed in the Ezh2-CKO retinas. The ectopic expression of Arf or Ink4a in the retina suppressed proliferation and increased apoptosis. In addition, earlier onset of Müller glia differentiation was observed in Ink4a-expressing cells. These results support an important role for histone H3K27me3 modification in regulating the proliferation and maturation of certain subsets of interneurons in the retina.

Original languageEnglish
Pages (from-to)947-60
Number of pages14
JournalDevelopmental Neurobiology
Volume75
Issue number9
DOIs
Publication statusPublished - Sep 2015
Externally publishedYes

Fingerprint

Histones
Retina
Knockout Mice
Histone Code
Neuroglia
Retinal Rod Photoreceptor Cells
Genetic Loci
Interneurons
Transcription Factors
Cell Proliferation
Apoptosis
Gene Expression

Keywords

  • Animals
  • Animals, Newborn
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16
  • Interneurons
  • Mice, Knockout
  • Neurogenesis
  • Neuroglia
  • Polycomb Repressive Complex 2
  • Retina
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Iida, A., Iwagawa, T., Baba, Y., Satoh, S., Mochizuki, Y., Nakauchi, H., ... Watanabe, S. (2015). Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation. Developmental Neurobiology, 75(9), 947-60. https://doi.org/10.1002/dneu.22261

Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation. / Iida, Atsumi; Iwagawa, Toshiro; Baba, Yukihiro; Satoh, Shinya; Mochizuki, Yujin; Nakauchi, Hiromitsu; Furukawa, Takahisa; Koseki, Haruhiko; Murakami, Akira; Watanabe, Sumiko.

In: Developmental Neurobiology, Vol. 75, No. 9, 09.2015, p. 947-60.

Research output: Contribution to journalArticle

Iida, A, Iwagawa, T, Baba, Y, Satoh, S, Mochizuki, Y, Nakauchi, H, Furukawa, T, Koseki, H, Murakami, A & Watanabe, S 2015, 'Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation', Developmental Neurobiology, vol. 75, no. 9, pp. 947-60. https://doi.org/10.1002/dneu.22261
Iida, Atsumi ; Iwagawa, Toshiro ; Baba, Yukihiro ; Satoh, Shinya ; Mochizuki, Yujin ; Nakauchi, Hiromitsu ; Furukawa, Takahisa ; Koseki, Haruhiko ; Murakami, Akira ; Watanabe, Sumiko. / Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation. In: Developmental Neurobiology. 2015 ; Vol. 75, No. 9. pp. 947-60.
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abstract = "The histone modification H3K27me3 regulates transcription negatively, and Jmjd3 and Ezh2 demethylate and methylate H3K27me3 and H3K27, respectively. We demonstrated previously that Jmjd3 plays pivotal roles in the differentiation of subsets of bipolar (BP) cells by regulating H3K27me3 levels at the Bhlhb4 and Vsx1 loci, both of which are transcription factors essential for the maturation of BP cell subsets. In this study, we examined the role of Ezh2 in retinal development using retina-specific Ezh2 conditional knockout mice (Ezh2-CKO). The eyes of the Ezh2-CKO mice were microphthalemic, and the proliferation of retinal cells was diminished postnatally in Ezh2-CKO. Differentiation of all examined retinal subsets was observed with higher proportion of BP cell subsets, which was determined by immunostaining using specific retinal markers. The onsets of M{\"u}ller glia and rod photoreceptor differentiation were accelerated. The expression of Bhlhb4 was increased in postnatal retinas, which was accompanied by the loss of H3K27me3 modifications at these genetic loci. Decreased expression of proneural genes in postnatal stage was observed. As reported previously in other Ezh2-KO tissues, increased expression of Arf/Ink4a was observed in the Ezh2-CKO retinas. The ectopic expression of Arf or Ink4a in the retina suppressed proliferation and increased apoptosis. In addition, earlier onset of M{\"u}ller glia differentiation was observed in Ink4a-expressing cells. These results support an important role for histone H3K27me3 modification in regulating the proliferation and maturation of certain subsets of interneurons in the retina.",
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