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Coordinated activities of EZH2 and EZH1 are essential for neurogenesis

ABSTRACT: Polycomb group proteins (PcG) are well known by their function in the regulation of developmental processes. PcG mediated regulation of genetic programs required for proper development are triggered by EZH2 H3K27 methyltransferase activity. EZH1 can partially substitute EZH2 activity. However, unlike EZH2, EZH1 is presence in differentiated and adult tissues suggesting additional biological functions. Here we show that EZH2 is predominantly expressed in neural stem cells being essential for neural stem cells self renewal and homeostasis. There, it controls the transcriptional state of cell cycle regulators, such as CIP1. But it is also necessary to regulate genes involved in surveillance and neuroepithelial polarity. In contrast, EZH1 expression is more abundant in differentiated cells within the spinal cord and its downregulation unables neural stem cells to differentiate. All together our data reveal a complementary but non-redundant role of EZH2 and EZH1 in neurogenesis.

ORGANISM(S): Gallus gallus

PROVIDER: GSE39450 | GEO | 2016/05/24

SECONDARY ACCESSION(S): PRJNA170905

REPOSITORIES: GEO

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Project description:Polycomb protein group (PcG)-dependent trimethylation on H3-K27(H3K27me3) regulates identity of embryonic stem cells (SCs). How H3K27me3 governs adult SCs and tissue development is unclear. Here, we conditionally target H3-K27-methyltransferases Ezh2 and Ezh1 to address their roles in mouse skin homeostasis. Postnatal phenotypes appear only in doubly-targeted skin, where H3K27me3 is abolished, revealing functional redundancy in EZH1/2 proteins. Surprisingly, while Ezh1/2-null hair follicles (HFs) arrest morphogenesis and degenerate due to defective proliferation and increased apoptosis, epidermis hyperproliferates and survives engraftment. mRNA-microarray studies reveal that despite these striking phenotypic differences, similar genes are upregulated in HF and epidermal Ezh1/2-null progenitors. Featured prominently are a) PcG-controlled non-skin lineage genes, whose expression is still significantly lower than in native tissues, and b) the PcG-regulated Ink4a/Inkb/Arf locus. Interestingly, even though Ink4a/Arf/Ink4b genes are fully activated in HF cells, they only partially so in epidermal-progenitors. Importantly, transduction of Ink4b/Ink4a/Arf shRNAs restores proliferation/survival of Ezh1/2-null HF progenitors in vitro, pointing towards the relevance of this locus to the observed HF phenotypes. Our findings reveal new insights into Polycomb-dependent tissue control and provide a new twist to how different progenitors within one tissue respond to loss of H3K27me3. RNAs from FACS-purified WT and Ezh1/2 2KO ORS, matrix and epidermal cells (Rendl et al., 2005) were provided to the Genomics Core Facility, MSKCC for quality control, quantification, reverse transcription, labeling and hybridization to MOE430A 2.0 microarray chips (Affymetrix). Arrays were scanned per the manufacturer’s specifications for the Affymetrix MOE430v2 chip. Images were background-subtracted. Probesets were identified as differentially expressed when the absolute fold change was ≥2. Probesets selected for visualization were log2 transformed and were analyzed with hierarchical clustering (Pearson correlation, average linkage), and visualized with heatmaps to assist in interpretation.

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Coordinated activities of EZH2 and EZH1 are essential for neurogenesis

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