Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark.
Mol Cell. 2010 Sep 24;39(6):886-900. doi: 10.1016/j.molcel.2010.08.020.
Epigenetic regulation of chromatin structure is essential for the expression of genes determining cellular specification and function. The Polycomb repressive complex 2 (PRC2) di- and trimethylates histone H3 on lysine 27 (H3K27me2/me3) to establish repression of specific genes in embryonic stem cells and during differentiation. How the Polycomb group (PcG) target genes are regulated by environmental cues and signaling pathways is quite unexplored. Here, we show that the mitogen- and stress-activated kinases (MSK), through a mechanism that involves promoter recruitment, histone H3K27me3S28 phosphorylation, and displacement of PcG proteins, lead to gene activation. We present evidence that the H3K27me3S28 phosphorylation is functioning in response to stress signaling, mitogenic signaling, and retinoic acid (RA)-induced neuronal differentiation. We propose that MSK-mediated H3K27me3S28 phosphorylation serves as a mechanism to activate a subset of PcG target genes determined by the biological stimuli and thereby modulate the gene expression program determining cell fate.
染色质结构的表观遗传调控对于决定细胞特化和功能的基因表达至关重要。多梳抑制复合物 2 (PRC2) 双甲基化和三甲基化组蛋白 H3 赖氨酸 27 (H3K27me2/me3)，以在胚胎干细胞和分化过程中建立对特定基因的抑制。多梳蛋白 (PcG) 靶基因如何受到环境线索和信号通路的调节还相当未知。在这里，我们表明，有丝分裂原和应激激活的激酶 (MSK) 通过涉及启动子募集、组蛋白 H3K27me3S28 磷酸化和 PcG 蛋白位移的机制，导致基因激活。我们提供的证据表明，H3K27me3S28 磷酸化是对应激信号、有丝分裂原信号和视黄酸 (RA) 诱导的神经元分化的反应。我们提出，MSK 介导的 H3K27me3S28 磷酸化作为一种机制，可激活一组由生物刺激决定的 PcG 靶基因，从而调节决定细胞命运的基因表达程序。
