EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair

Abstract

Polycomb protein group (PcG)-dependent trimethylation on H3K27 (H3K27me3) regulates identity of embryonic stem cells (ESCs). How H3K27me3 governs adult SCs and tissue development is unclear. Here, we conditionally target H3K27 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 up-regulated in HF and epidermal Ezh1/2-null progenitors. Featured prominently are (1) PcG-controlled nonskin lineage genes, whose expression is still significantly lower than in native tissues, and (2) the PcG-regulated Ink4a/Inkb/Arf locus. Interestingly, when EZH1/2 are absent, even though Ink4a/Arf/Ink4b genes are fully activated in HF cells, they are 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 toward 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.

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

“…This is in contrast to ES cells and the early embryo, where growth after complete loss of PRC2 function is compromised, but not abolished (16,26,33). PRC2 function has also been shown to be dispensable for proliferation of Ezh1/Ezh2 double-knockout cells in the epidermis proper but required in the hair follicle (27). In summary, available data illustrate that the consequences of partial and complete loss of PRC2 function are context dependent.…”

“…This loss is accompanied by derepression of polycomb targets silenced by persistent H3K27me3 in Ezh2-null leukemic cells and by attenuated expression of a Myc module with documented importance in cancer. These gene expression changes are accompanied by failure of Eed-null leukemic cells to proliferate in vivo, demonstrating that in contrast to murine ES cells (16,26) and murine epidermis (27), MLL-AF9 leukemia strictly depends on PRC2 function.…”

The Polycomb Protein Ezh2 Impacts on Induced Pluripotent Stem Cell Generation

“…But some H3K27me3 remained, probably due to compensation by other methyltransferases, such as Ezh1. Functional redundancy between Ezh1 and Ezh2 was described before [8,40]. All this indicates that Ezh2 is critical for induction of pluripotency, but once pluripotency is established, Ezh2 is not required anymore.…”

In situ histone landscape of nephrogenesis

“…One possible reason for enrichment of Ezh2 in the cap mesenchyme is the necessity of Ezh2 to maintain the identity of the Six2 population and to exert tight control over self-renewal and differentiation, as has been described in the skin. 31 G9a is a histone lysine 9 KMT and catalyzes the formation of H3K9me2, a repressive chromatin mark. 32 Staining for Pax2 and G9a demonstrated co-localization within the nephrogenic zone (Fig.…”