Polycomb repressive complex 2 impedes intestinal cell terminal differentiation
Polycomb repressive complex 2 impedes intestinal cell terminal differentiation
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DOI：
10.1242/jcs.102061
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发表时间：
2012-07-15
影响因子：
4
通讯作者：
Beaulieu, Jean-Francois
中科院分区：
文献类型：
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作者：
Benoit, Yannick D.;Lepage, Manon B.;Beaulieu, Jean-Francois
隐窝-绒毛轴是小肠的功能单位，成熟的吸收细胞局限于绒毛，干细胞和过渡扩增细胞及分化细胞局限于隐窝。多梳群(PcG)蛋白抑制胚胎干细胞分化并促进其自我更新。PCGS通过多梳抑制复合体2(PRC2)的作用催化表观遗传修饰，例如组蛋白尾部甲基的共价加成，从而防止转录活性。尽管PCGS在保存茎的特性方面的作用现在已经被很好地确立，但最近的证据表明，它们可能也参与了分化的调节。使用概括肠细胞分化计划的肠上皮细胞模型，我们产生了RNAi介导的稳定的SUZ12基因敲除，它构成了PRC2组装和功能的基石，以分析肠道细胞的增殖和分化。对SUZ12在人类肠道组织中的表达也进行了研究，发现SUZ12存在于大多数隐窝增殖的上皮细胞中，并且在结直肠癌中的表达增加。此外，在肠道细胞模型中，PRC2的中断导致了许多末端分化标志物的显著早熟表达。综上所述，我们的数据确定了PcG蛋白参与抑制肠细胞分化程序的机制，并表明在运输放大细胞群中存在类似的机制来减缓末端分化。
The crypt-villus axis constitutes the functional unit of the small intestine, where mature absorptive cells are confined to the villi, and stem cells and transit amplifying and differentiating cells are restricted to the crypts. The polycomb group (PcG) proteins repress differentiation and promote self-renewal in embryonic stem cells. PcGs prevent transcriptional activity by catalysing epigenetic modifications, such as the covalent addition of methyl groups on histone tails, through the action of the polycomb repressive complex 2 (PRC2). Although a role for PcGs in the preservation of stemness characteristics is now well established, recent evidence suggests that they may also be involved in the regulation of differentiation. Using intestinal epithelial cell models that recapitulate the enterocytic differentiation programme, we generated a RNAi-mediated stable knockdown of SUZ12, which constitutes a cornerstone for PRC2 assembly and functionality, in order to analyse intestinal cell proliferation and differentiation. Expression of SUZ12 was also investigated in human intestinal tissues, revealing the presence of SUZ12 in most proliferative epithelial cells of the crypt and an increase in its expression in colorectal cancers. Moreover, PRC2 disruption led to a significant precocious expression of a number of terminal differentiation markers in intestinal cell models. Taken together, our data identified a mechanism whereby PcG proteins participate in the repression of the enterocytic differentiation program, and suggest that a similar mechanism exists in situ to slow down terminal differentiation in the transit amplifying cell population.