Abstract
JARID2 is a noncatalytic member of the polycomb repressive complex 2 (PRC2) which methylates of histone 3 lysine 27 (H3K27). In this work, we show that JARID2 and the PRC2 complex regulate the cell cycle in skeletal muscle cells to control proliferation and mitotic exit. We found that the stable depletion of JARID2 leads to increased proliferation and cell accumulation in S phase. The regulation of the cell cycle by JARID2 is mediated by direct repression of both cyclin D1 and cyclin E1, both of which are targets of PRC2-mediated H3K27 methylation. Intriguingly, we also find that the retinoblastoma protein (RB1) is a direct target of JARID2 and the PRC2 complex. The depletion of JARID2 is not sufficient to activate RB1. However, the ectopic expression of RB1 can suppress cyclin D1 expression in JARID2-depleted cells. Transient depletion of JARID2 in skeletal muscle cells leads to a transient up-regulation of cyclin D1 that is quickly suppressed with no resulting effect on proliferation, Taken together, we show that JARID2 and the PRC2 complex regulate skeletal muscle proliferation in a precise manner that involves the repression of cyclin D1, thus restraining proliferation and repressing RB1, which is required for mitotic exit and terminal differentiation.
Highlights
JARID2 is a noncatalytic member of the polycomb repressive complex 2 (PRC2) which methylates of histone 3 lysine 27 (H3K27)
We show that JARID2 and the PRC2 complex regulate the cell cycle in skeletal muscle cells to control proliferation and mitotic exit
Transient depletion of JARID2 in skeletal muscle cells leads to a transient up-regulation of cyclin D1 that is quickly suppressed with no resulting effect on proliferation, Taken together, we show that JARID2 and the PRC2 complex regulate skeletal muscle proliferation in a precise manner that involves the repression of cyclin D1, restraining proliferation and repressing RB1, which is required for mitotic exit and terminal differentiation
Summary
We found that restoration of JARID2 down-regulated cyclin D1 at the mRNA (Fig. 4D), and protein (Fig. 4E) level, confirming that JARID2 controls the expression of cyclin D1 in skeletal muscle cells. As we observed with a transient EZH2 depletion, the negative cell cycle regulator Cdkn1a (p21) was up-regulated (Fig. 8I), and this effect could be seen at the protein level (Fig. 8H). Our results confirm that JARID2 directly regulates cyclin D1 through the PRC2 complex, but because of the complex effects on both positive and negative cell cycle genes, sustained depletion is required to see a sustained activation of cyclin D1 and enhanced proliferation
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