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

Abstract

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.

Deletion of histone demethylase Lsd1 (Kdm1a) during retinal development leads to defects in retinal function and structure

“…Histone modifiers, such as the demethylases JMJD3, UTX, and LSD1, provide additional regulation. For example, the loss of JMJD3 and UTX affects the proper development of inner retinal cells such as bipolar, amacrine, and horizontal cells (Iida et al, 2014;Iwagawa et al, 2020;Umutoni et al, 2020). Lsd1 inhibition directly impacts the survival of specific retinal cells, such as RGCs and photoreceptors (Tsutsumi et al, 2016;Popova et al, 2021), and alters regulation of microRNAs, such as the miR-21-5p/NLRP12 axis, to facilitate RGC pyroptosis (Yu et al, 2022).…”

Increased H3K27 trimethylation contributes to cone survival in a mouse model of cone dystrophy

“…As the chromatin in mouse rods is already hypercondensed, the upregulation of repressive methylation marks such as H3K27me3 push nuclei towards pyknosis and subsequent cell death [ 45 ], while the same disease mechanism may not happen in mouse cones due to their different natural chromatin condensation. The role of H3K27me3 and their corresponding demethylases is complex, with studies showing the role of Kdm6b (a demethylase of H3K27me3) in the development of the earlier born retinal cells; amacrine, horizontal, retinal ganglion cells as well as rod bipolar cells [ 46 ]. Raeisossadati et al 2019 also showed that injection of GSK-J1 in PN (Postnatal day) 0 mice identified an integral role for Kdm6b in processes such as cell proliferation, apoptosis, differentiation, senescence and cellular reprogramming [ 47 ].…”

Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates Paclitaxel-Induced Neuropathic Pain

“…Trimethylation of histone H3 at lysine 27 (H3K27me3) is a mediator of transcriptional gene repression, and the Jumonji family (Jmj family) member jumonji domain-containing protein D3 (JMJD3) is a demethylase specific to H3K27me3. 13 The H3K27me3 demethylase JMJD3 is implicated in neurological lesion-induced chronic pain. 14 In contrast, the Trpv1 promoter is regulated by H3K27me3.…”