Regulation of Retinal Development via the Epigenetic Modification of Histone H3

Watanabe, Sumiko; Murakami, Akira

doi:10.1007/978-3-319-17121-0_84

Cited by 9 publications

(10 citation statements)

References 6 publications

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“…Although a redundant phenotype was observed in loss of function of Utx or Jmjd3 , Jmjd3/Utx-cDKO mice did not show complete loss of PKCα-positive rod-ON-BCs. 37 In this study, we observed reductions in the numbers of ACs and RGCs in the Jmjd3-cKO retina. Although both demethylases are strongly expressed in postnatal RGCs and ACs, the Jmjd3/Utx-cDKO retina showed a reduction, but not a complete loss, of RGCs and ACs; currently, we do not know the underlying mechanism.…”

Section: Discussionsupporting

confidence: 49%

“…Utx is another H3K27me3-specific demethylase that is expressed in the INL and GCL during retinal development. 37 We found that the numbers of BRN3B-positive RGCs and TFAP2A-positive ACs were not reduced in the Utx-cKO retina ( Supplementary Figs. S5 A–D).…”

Section: Resultsmentioning

confidence: 86%

“…Recently, we found that another H3K27me3 demethylase, Utx, is also required for the development of rod-ON-BCs in a manner similar to that of Jmjd3 . 37 Because the gross expression patterns of Jmjd3 and Utx are different, we surmised that Utx might divide demethylation in retinal development and regulate retinal cells other than BCs. Therefore one important question that remains to be addressed is whether other lineages of retinal cells (such as photoreceptors or Müller glia) require demethylation of H3K27me3 for differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Jmjd3 Plays Pivotal Roles in the Proper Development of Early-Born Retinal Lineages: Amacrine, Horizontal, and Retinal Ganglion Cells

Iwagawa

Honda

Watanabe

2020

Invest. Ophthalmol. Vis. Sci.

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Trimethylation of histone H3 at lysine 27 (H3K27me3) is a critical mediator of transcriptional gene repression, and Jmjd3 and Utx are the demethylases specific to H3K27me3. Using an in vitro retinal explant culture system, we previously revealed the role of Jmjd3 in the development of rod bipolar cells; however, the roles of Jmjd3 in the development of early-born retinal cells are unknown due to limitations concerning the use of retinal explant culture systems. In this study, we investigated the roles of Jmjd3 in the development of early-born retinal cells. METHODS. We examined retina-specific conditional Jmjd3 knockout (Jmjd3-cKO) mice using immunohistochemistry and quantitative reverse transcription PCR and JMJD3 binding to a target locus by chromatin immunoprecipitation analysis. RESULTS. We observed reductions in amacrine cells (ACs) and horizontal cells (HCs), as well as lowered expression levels of several transcription factors involved in the development of ACs and HCs in the Jmjd3-cKO mouse retina. JMJD3 bound the promoter regions of these transcription factors. Notably, an elevated number of retinal ganglion cells (RGCs) was observed at embryonic stages, whereas RGCs were moderately reduced at later postnatal stages in the Jmjd3-cKO retina. We also observed reduced expression of Eomes, which is required for the maintenance of RGCs, as well as lower H3K27me3 level and lower JMJD3 binding in the promoter region of Eomes in RGCenriched cells. CONCLUSIONS. The results indicated that Jmjd3 has critical roles in the development of early-born retinal subtypes, and suggested biphasic roles of Jmjd3 in RGC production and maintenance.

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Section: Discussionsupporting

confidence: 49%

Section: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Jmjd3 Plays Pivotal Roles in the Proper Development of Early-Born Retinal Lineages: Amacrine, Horizontal, and Retinal Ganglion Cells

Iwagawa

Honda

Watanabe

2020

Invest. Ophthalmol. Vis. Sci.

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“…While its underlying mechanisms remain uncertain, in part, this is unlikely to be caused solely by the spatiotemporal dynamics and cooperative functionalities of other HMTs and demethylases. Among the two HMTs that regulate H3K27 trimethylation, Ezh1 and Ezh2 , and the demethylase Jmjd3 , Ezh2 and Jmjd3 are widely expressed in retinal progenitors during development; Ezh1 is expressed only weakly in the postnatal retina 29 . The transient expression of Ezh2 during development, which is completely repressed postnatally in the retina, was also confirmed during human retinal development 11 .…”

Section: Discussionmentioning

confidence: 99%

Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1

Yan

Cheng

Cho

et al. 2016

Sci Rep

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Some adult-onset disorders may be linked to dysregulated embryonic development, yet the mechanisms underlying this association remain poorly understood. Congenital retinal degenerative diseases are blinding disorders characterized by postnatal degeneration of photoreceptors, and affect nearly 2 million individuals worldwide, but ∼50% do not have a known mutation, implicating contributions of epigenetic factors. We found that embryonic deletion of the histone methyltransferase (HMT) Ezh2 from all retinal progenitors resulted in progressive photoreceptor degeneration throughout postnatal life, via derepression of fetal expression of Six1 and its targets. Forced expression of Six1 in the postnatal retina was sufficient to induce photoreceptor degeneration. Ezh2, although enriched in the embryonic retina, was not present in the mature retina; these data reveal an Ezh2-mediated feed-forward pathway that is required for maintaining photoreceptor homeostasis in the adult and suggest novel targets for retinal degeneration therapy.

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“…In this study, we investigated the role of UTX during retinal development by the loss of function of UTX using in vivo and ex vivo retinal differentiation systems. We previously obtained preliminary results showing that the loss of UTX in the retinal explant resulted in the failed differentiation of PKCα‐positive rod ON‐bipolar cells (Watanabe & Murakami, 2016). In this study, like JMJD3, we found that the loss of UTX also resulted in a reduced number of PKCα‐positive rod ON‐bipolar cells.…”

Section: Introductionmentioning

confidence: 99%

H3K27me3 demethylase UTX regulates the differentiation of a subset of bipolar cells in the mouse retina

et al. 2020

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Di‐ and trimethylation of lysine 27 on histone 3 (H3K27me2/3) is a critical gene repression mechanism. We previously showed that down‐regulation of the H3K27 demethylase, Jumonji domain‐containing protein 3 (JMJD3), resulted in a reduced number of protein kinase C (PKC)α‐positive rod ON‐bipolar cells. In this work, we focused on the role of another H3K27 demethylase, ubiquitously transcribed tetratricopeptide repeat X chromosome (UTX), in retinal development. UTX was expressed in the retinal progenitor cells of the embryonic mouse retina and was observed in the inner nuclear layer during late retinal development and in the mature retina. The short hairpin RNA‐mediated knockdown of Utx in a mouse retinal explant led to a reduced number of PKCα‐positive rod ON‐bipolar cells. However, other retinal subtypes were unaffected by this knockdown. Using a retina‐specific knockout of Utx in mice, the in vivo effects of UTX down‐regulation were examined. Again, the number of PKCα‐positive rod ON‐bipolar cells was reduced, and no other apparent phenotypes, including retinal progenitor proliferation, apoptosis or differentiation, were observed. Finally, we examined retina‐specific Utx and Jmjd3 double‐knockout mice and found that although the number of rod ON‐bipolar cells was reduced, no additional effects from the loss of Utx and Jmjd3 were observed. Taken together, our data show that UTX contributes to retinal differentiation in a lineage‐specific manner.

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Regulation of Retinal Development via the Epigenetic Modification of Histone H3

Cited by 9 publications

References 6 publications

Jmjd3 Plays Pivotal Roles in the Proper Development of Early-Born Retinal Lineages: Amacrine, Horizontal, and Retinal Ganglion Cells

Jmjd3 Plays Pivotal Roles in the Proper Development of Early-Born Retinal Lineages: Amacrine, Horizontal, and Retinal Ganglion Cells

Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1

H3K27me3 demethylase UTX regulates the differentiation of a subset of bipolar cells in the mouse retina

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