Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium.
Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium.
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DOI：
10.1083/jcb.201506065
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发表时间：
2016-01-04
期刊：
影响因子：
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通讯作者：
Botchkarev VA
中科院分区：
文献类型：
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作者：
Mardaryev AN;Liu B;Rapisarda V;Poterlowicz K;Malashchuk I;Rudolf J;Sharov AA;Jahoda CA;Fessing MY;Benitah SA;Xu GL;Botchkarev VA
多梳复合体成员Cbx 4抑制表皮角质形成细胞中非表皮谱系和细胞周期抑制剂基因，并作为直接p63靶点发挥作用，维持发育中表皮的上皮身份和增殖活性。在发育过程中，多能祖细胞建立了谱系特异性的基因激活和沉默程序，这些程序是其分化为特化细胞类型的基础。我们发现，Polycomb组件Cbx 4作为一个关键的决定因素，保持上皮身份的发展表皮抑制非表皮基因表达程序。小鼠中的Cbx 4消融导致表皮厚度和角质形成细胞（KC）增殖显著降低，这与许多神经元基因和编码细胞周期蛋白依赖性激酶抑制剂（p16/p19和p57）的基因的激活有关。此外，染色体结构域和SUMO E3连接酶依赖的Cbx 4活性差异调节KC中非表皮基因的增殖、分化和表达。最后，Cbx 4在KC中的表达直接受p63转录因子的调节，而Cbx 4过表达能够部分挽救p63消融对表皮发育的影响。这些数据表明，Cbx 4在p63调控的表皮分化程序中起着至关重要的作用，通过抑制所选的非表皮谱系和细胞周期抑制因子基因来维持KC中的上皮身份和增殖活性。
Polycomb complex member Cbx4 represses nonepidermal lineage and cell cycle inhibitor genes in the epidermal keratinocytes and operates as a direct p63 target, maintaining epithelial identity and proliferative activity in the developing epidermis. During development, multipotent progenitor cells establish lineage-specific programmers of gene activation and silencing underlying their differentiation into specialized cell types. We show that the Polycomb component Cbx4 serves as a critical determinant that maintains the epithelial identity in the developing epidermis by repressing nonepidermal gene expression programs. Cbx4 ablation in mice results in a marked decrease of the epidermal thickness and keratinocyte (KC) proliferation associated with activation of numerous neuronal genes and genes encoding cyclin-dependent kinase inhibitors (p16/p19 and p57). Furthermore, the chromodomain- and SUMO E3 ligase–dependent Cbx4 activities differentially regulate proliferation, differentiation, and expression of nonepidermal genes in KCs. Finally, Cbx4 expression in KCs is directly regulated by p63 transcription factor, whereas Cbx4 overexpression is capable of partially rescuing the effects of p63 ablation on epidermal development. These data demonstrate that Cbx4 plays a crucial role in the p63-regulated program of epidermal differentiation, maintaining the epithelial identity and proliferative activity in KCs via repression of the selected nonepidermal lineage and cell cycle inhibitor genes.