Histone demethylase Jmjd3 is required for the development of subsets of retinal bipolar cells

Abstract

Di-and trimethylation of lysine 27 on histone H3 (H3K27me2/3) is an important gene repression mechanism. H3K27me2/3-specific demethylase, Jmjd3, was expressed in the inner nuclear layer during late retinal development. In contrast, H3K27 methyltransferase, Ezh2, was highly expressed in the embryonic retina but its expression decreased rapidly after birth. Jmjd3 loss of function in the developing retina resulted in failed differentiation of PKC-positive bipolar cell subsets (rod-ON-BP) and reduced transcription factor Bhlhb4 expression, which is critical for the differentiation of rod-ON-BP cells. Overexpression of Bhlhb4, but not of other BP cell-related genes, such as transcription factors Neurod and Chx10, in Jmjd3-knockdown retina rescued loss of PKC-positive BP cells. Populations of other retinal cell subsets were not significantly affected. In addition, proliferation activity and apoptotic cell number during retinal development were not affected by the loss of Jmjd3. Levels of histone H3 trimethyl Lys27 (H3K27me3) in the Bhlhb4 locus were lower in Islet-1-positive BP cells and amacrine cells than in the Islet-1-negative cell fraction. The Islet-1-negative cell fraction consisted mainly of photoreceptors, suggestive of lineage-specific demethylation of H3K27me3 in the Bhlhb4 locus. We propose that lineage-specific H3K27me3 demethylation of critical gene loci by spatiotemporal-specific Jmjd3 expression is required for appropriate maturation of retinal cells.histone methylation | progenitor | interneuron

Regulation of Retinal Development via the Epigenetic Modification of Histone H3

“…For that purpose, we examined changes in histone modification and employed a loss-of-function analysis to reveal the roles of histone H3 methylases and demethylases during retinal development. This article summarizes the main findings presented in Poster 149 at the RD2014 meeting and published in 2014 (Iida et al 2014). Additional data related to this issue are presented and discussed.…”

“…ChIP assay was done as described previously (Iida et al 2014). Control IgG experiments gave only negligible values.…”

“…Antibodies used are anti-acetyl Histone H3 (acetylH3, Millipore 06-599177), -Histone H3 tri-methyl Lys27 (H3K27me3, Abcam6002205), and -Histone H3 tri-methyl Lys27 (H3K4me3, active motif 39159178) antibodies. Immunostaining of frozen sections was done as described previously (Iida et al 2014). …”

“…We created an sh-RNA-mediated loss-of-function of Jmjd3 using retinal explants (Iida et al 2014). The down-regulation of Jmjd3 in developing retina resulted in a failure of progenitor cells to differentiate to protein kinase C (PKC)-positive bipolar cell subsets (rod-ON-BP), and it reduced the expression of Bhlhb4, which is critical for the differentiation of rod-ON-BP cells (Iida et al 2014). Furthermore, the H3K-27me3 level at the Bhlhb4 locus was specifically lower in a bipolar cell-enriched fraction.…”

The Histone Demethylase UTX Promotes Brown Adipocyte Thermogenic Program Via Coordinated Regulation of H3K27 Demethylation and Acetylation

“…UTX is a histone H3K27-specific demethylase that preferentially demethylates tri-methylated H3K27 and therefore relieves its ability to silence the genes, leading to activation of the gene transcription (25,26). H3K27 methylation (H3K27me) has been implicated in the regulation of development of a number of cell types (27)(28)(29)(30). In this study, we first determined the expression of UTX during the brown adipocyte differentiation in vitro and in response to sympathetic activation via cold exposure in vivo.…”