Epithelial Cell Biology Group, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, UK.
Nat Cell Biol. 2012 Jun 24;14(7):753-63. doi: 10.1038/ncb2520.
It is becoming clear that interconnected functional gene networks, rather than individual genes, govern stem cell self-renewal and differentiation. To identify epigenetic factors that impact on human epidermal stem cells we performed siRNA-based genetic screens for 332 chromatin modifiers. We developed a Bayesian mixture model to predict putative functional interactions between epigenetic modifiers that regulate differentiation. We discovered a network of genetic interactions involving EZH2, UHRF1 (both known to regulate epidermal self-renewal), ING5 (a MORF complex component), BPTF and SMARCA5 (NURF complex components). Genome-wide localization and global mRNA expression analysis revealed that these factors impact two distinct but functionally related gene sets, including integrin extracellular matrix receptors that mediate anchorage of epidermal stem cells to their niche. Using a competitive epidermal reconstitution assay we confirmed that ING5, BPTF, SMARCA5, EZH2 and UHRF1 control differentiation under physiological conditions. Thus, regulation of distinct gene expression programs through the interplay between diverse epigenetic strategies protects epidermal stem cells from differentiation.
很明显，相互关联的功能基因网络而非单个基因控制着干细胞的自我更新和分化。为了鉴定影响人类表皮干细胞的表观遗传因子，我们针对 332 种染色质修饰物进行了基于 siRNA 的遗传筛选。我们开发了一种贝叶斯混合模型来预测调节分化的表观遗传修饰物之间的潜在功能相互作用。我们发现了一个涉及 EZH2、UHRF1（两者都已知调节表皮自我更新）、ING5（MORF 复合物成分）、BPTF 和 SMARCA5（NURF 复合物成分）的遗传相互作用网络。全基因组定位和全局 mRNA 表达分析表明，这些因子影响两个不同但功能相关的基因集，包括整合素细胞外基质受体，其介导表皮干细胞与其龛位的锚定。使用竞争性表皮再生成测定法，我们证实 ING5、BPTF、SMARCA5、EZH2 和 UHRF1 在生理条件下控制分化。因此，通过不同表观遗传策略的相互作用调节不同的基因表达程序可保护表皮干细胞免受分化。
