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

Abstract

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.

Lysine Demethylase KDM6A in Differentiation, Development, and Cancer

“…A recent study also suggests that KDM6A is important for the differentiation of a subset of retinal cells. In particular, retina-specific knockout of KDM6A using Dkk3-Cre mice leads to a reduction in protein kinase C␣ (PKC␣)-positive rod "on" bipolar cells in postnatal day 10 mouse retinas while having no effect on retinal progenitor cell proliferation (39). Using a CRISPR-Cas9 KO system in C2C12 myoblasts to screen a group of candidate lysine demethylases, a group reported that KDM6A was required for osteoblast differentiation in culture (40).…”

UTX deficiency in neural stem/progenitor cells results in impaired neural development, fetal ventriculomegaly, and postnatal death

“…[39][40][41] To determine the tissue-specific role of UTX, we generated Utx flox/flox mice and crossed them with different Cre lines. We demonstrated that UTX deficiency accelerates bladder cancer development by activating proinflammatory molecules, 42 results in decrease of PKCα-positive rod ON-bipolar cells without affecting retinal progenitor proliferation, 43 and induces hematopoietic aging by globally converting the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. 44 In this study, we aimed to clarify the role of UTX in the neural system by crossing Utx flox/flox mice with mice expressing Cre in NSPCs.…”

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).…”