EED, a member of the polycomb group, is required for nephron differentiation and the maintenance of nephron progenitor cells

Abstract

Epigenetic regulation of gene expression has a crucial role allowing for the self-renewal and differentiation of stem and progenitor populations during organogenesis. The mammalian kidney maintains a population of self-renewing stem cells that differentiate to give rise to thousands of nephrons, which are the functional units that carry out filtration to maintain physiological homeostasis. The polycomb repressive complex 2 (PRC2) epigenetically represses gene expression during development by placing the H3K27me3 mark on histone H3 at promoter and enhancer sites, resulting in gene silencing. To understand the role of PRC2 in nephron differentiation, we conditionally inactivated the gene, which encodes a nonredundant component of the PRC2 complex, in nephron progenitor cells. Resultant kidneys were smaller and showed premature loss of progenitor cells. The progenitors in mutant mice that were induced to differentiate did not develop into properly formed nephrons. , normally expressed in the renal vesicle, was overexpressed in kidneys of mutant mice. Thus, PRC2 has a crucial role in suppressing the expression of genes that maintain the progenitor state, allowing nephron differentiation to proceed.

Effects of Environmental Conditions on Nephron Number: Modeling Maternal Disease and Epigenetic Regulation in Renal Development

“…The results of this work as well as previous works suggest that epigenetic mechanisms play a role in kidney development [ 30 , 40 , 41 , 42 , 43 , 44 , 45 ]. Therefore, we wanted to systematically evaluate the effect of epigenetic modulators of the different enzyme classes on renal development.…”

Defining the dynamic chromatin landscape of mouse nephron progenitors

“…We speculate that these maturational changes in chromatin accessibility are likely orchestrated by concomitant changes in the epigenetic machinery such as the Polycomb complex, ATP-dependent chromatin remodelers, DNA methylation and the NuRD/HDAC complex, that govern the access of master regulators to their cis-acting elements. Indeed, there is genetic evidence that perturbations of the epigenetic machinery disrupt the balance between NPC proliferation and differentiation in vivo (Denner and Rauchman, 2013; El-Dahr and Saifudeen, 2018; Liu et al, 2018; Zhang et al, 2018). A caveat in this study is that ChIP-seq was performed on E13 and P0 NPC cultured in NPEM for two passages.…”

Epigenetic regulation of kidney progenitor cells

“…Eed KO resulted in smaller kidneys and premature loss of NPCs, and the investigators revealed a dual role of PRC2: it is required to maintain self-renewal of the NPCs; during differentiation, it might also be involved in repressing self-renewal genes, like Six2, to facilitate proper nephron differentiation. 15 However, the direct target genes regulated by PRC2 remains to be determined.…”