Polycomb repression complex 2 is required for the maintenance of retinal progenitor cells and balanced retinal differentiation

Abstract

Polycomb repressive complexes maintain transcriptional repression of genes encoding crucial developmental regulators through chromatin modification. Here we investigated the role of Polycomb repressive complex 2 (PRC2) in retinal development by inactivating its key components Eed and Ezh2. Conditional deletion of Ezh2 resulted in a partial loss of PRC2 function and accelerated differentiation of Müller glial cells. In contrast, inactivation of Eed led to the ablation of PRC2 function at early postnatal stage. Cell proliferation was reduced and retinal progenitor cells were significantly decreased in this mutant, which subsequently caused depletion of Müller glia, bipolar, and rod photoreceptor cells, primarily generated from postnatal retinal progenitor cells. Interestingly, the proportion of amacrine cells was dramatically increased at postnatal stages in the Eed-deficient retina. In accordance, multiple transcription factors controlling amacrine cell differentiation were upregulated. Furthermore, ChIP-seq analysis showed that these deregulated genes contained bivalent chromatin (H3K27me3 H3K4me3). Our results suggest that PRC2 is required for proliferation in order to maintain the retinal progenitor cells at postnatal stages and for retinal differentiation by controlling amacrine cell generation.

MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity

“…Overall, however, our findings are consistent with published reports demonstrating that MLL, the human orthologue of MLL1, is required for both S-phase entry and M-phase progression in cultured human cancer cell lines, acting at the G1/S and G2/M transitions 38 . Although the molecular differences between normal and Mll1 -deficient RPCs remain to be determined, similar RPC proliferation deficits were also seen in vertebrate retinas lacking several other histone modifying enzymes, particularly those involving the repressive histone mark H3K27me3 52 – 55 . This suggests the importance of homeostasis of histone modifying enzymes in retinogenesis.…”

“…Finally, Mll1KO affected retinal cell types significantly differ from those conditional knockouts of other histone modifying enzymes. Deficiency of the enzymes regulating the repressive mark H3K27me3, such as EED and EZH2 in the polycomb repressive complex 2 (RPC2), causes deficits in BCs, Rods and MGs 52 , 61 . Together, these findings emphasize the need to elucidate overlapping and unique roles of individual histone modifying enzymes and their homeostasis in the development and maintenance of particular cell types/tissues.…”

Temporal scaling in developmental gene networks by epigenetic timing control

“…Our gene network modeling leads us to propose that epigenetic-modifying factors act as master controllers of developmental speed and organism size ( Figure 6D-E networks Lee et al, 2006) ; consequently, the developmental schedules set by these networks could then be uniformly scaled by simply varying the activity of a single chromatin regulator acting globally on all network nodes. Consistent with this idea, disruptions in polycomb complex activity have been shown to accelerate differentiation across multiple cell lineages in different contexts (Akiyama et al, 2016;Endoh et al, 2017;Ezhkova et al, 2009;Fujimura et al, 2018;Jacobsen et al, 2017;Zhang et al, 2015) . In particular, deletion of the PRC2 methyltransferase Ezh2 accelerates the temporal schedule for cerebral corticogenesis, leading to reduced cortical tissue size while preserving the temporal order of neuronal subtype differentiation (Pereira et al, 2010) .…”

DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice

“…Ezh2 is dynamically expressed during retinal development, it is enriched in retinal progenitors and downregulated in differentiated cells, by P10 Ezh2 expression is largely restricted to the ganglion cell layer (GCL) and inner nuclear layer (INL), and then extinguished around P30 24 , 27 , 31 . Four studies used different mouse Cre strains to conditionally knock out Ezh2 or Eed in mouse retina to investigate the role of H3K27me3 in retina 24 , 27 , 31 , 54 . While knocking out Ezh2 in post-mitotic retinal ganglion cells (RGCs) has no major phenotypes 27 , inactivation of Ezh2 or Eed in retinal progenitors leads to abnormal differentiation of late-born retinal cells (rods, bipolar and Müller glial cells) in the early postnatal stages, and reduced overall eye size and ONL thickness at later postnatal stages, maybe due to reduced progenitor pool and/or enhanced cell death 24 , 27 , 31 , 54 .…”

“…Four studies used different mouse Cre strains to conditionally knock out Ezh2 or Eed in mouse retina to investigate the role of H3K27me3 in retina 24 , 27 , 31 , 54 . While knocking out Ezh2 in post-mitotic retinal ganglion cells (RGCs) has no major phenotypes 27 , inactivation of Ezh2 or Eed in retinal progenitors leads to abnormal differentiation of late-born retinal cells (rods, bipolar and Müller glial cells) in the early postnatal stages, and reduced overall eye size and ONL thickness at later postnatal stages, maybe due to reduced progenitor pool and/or enhanced cell death 24 , 27 , 31 , 54 . Thus low level of H3K27me3 in wt progenitors may not favor the survival of photoreceptors later.…”