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首页> 外文期刊>Epigenetics & Chromatin >EZH2-dependent chromatin looping controls INK4a and INK4b, but not ARF, during human progenitor cell differentiation and cellular senescence
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EZH2-dependent chromatin looping controls INK4a and INK4b, but not ARF, during human progenitor cell differentiation and cellular senescence

机译：在人类祖细胞分化和细胞衰老过程中，依赖EZH2的染色质环控制INK4a和INK4b，但不控制ARF

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Background The INK4b-ARF-INK4a tumour suppressor locus controls the balance between progenitor cell renewal and cancer. In this study, we investigated how higher-order chromatin structure modulates differential expression of the human INK4b-ARF-INK4a locus during progenitor cell differentiation, cellular ageing and senescence of cancer cells. Results We found that INK4b and INK4a, but not ARF, are upregulated following the differentiation of haematopoietic progenitor cells, in ageing fibroblasts and in senescing malignant rhabdoid tumour cells. To investigate the underlying molecular mechanism we analysed binding of polycomb group (PcG) repressive complexes (PRCs) and the spatial organization of the INK4b-ARF-INK4a locus. In agreement with differential derepression, PcG protein binding across the locus is discontinuous. As we described earlier, PcG repressors bind the INK4a promoter, but not ARF. Here, we identified a second peak of PcG binding that is located ~3 kb upstream of the INK4b promoter. During progenitor cell differentiation and ageing, PcG silencer EZH2 attenuates, causing loss of PRC binding and transcriptional activation of INK4b and INK4a. The expression pattern of the locus is reflected by its organization in space. In the repressed state, the PRC-binding regions are in close proximity, while the intervening chromatin harbouring ARF loops out. Down regulation of EZH2 causes release of the ~35 kb repressive chromatin loop and induction of both INK4a and INK4b, whereas ARF expression remains unaltered. Conclusion PcG silencers bind and coordinately regulate INK4b and INK4a, but not ARF, during a variety of physiological processes. Developmentally regulated EZH2 levels are one of the factors that can determine the higher order chromatin structure and expression pattern of the INK4b-ARF-INK4a locus, coupling human progenitor cell differentiation to proliferation control. Our results revealed a chromatin looping mechanism of long-range control and argue against models involving homogeneous spreading of PcG silencers across the INK4b-ARF-INK4a locus.
机译：背景技术INK4b-ARF-INK4a抑癌基因座控制着祖细胞更新与癌症之间的平衡。在这项研究中，我们调查了祖细胞分化，细胞衰老和癌细胞衰老过程中高级染色质结构如何调节人INK4b-ARF-INK4a基因座的差异表达。结果我们发现在造血祖细胞分化，衰老的成纤维细胞和衰老的恶性横纹肌瘤肿瘤细胞中，INK4b和INK4a而非ARF被上调。为了研究潜在的分子机制，我们分析了聚梳基团（PcG）阻抑复合物（PRC）的结合以及INK4b-ARF-INK4a基因座的空间组织。与差异抑制相关，PcG蛋白在整个基因座的结合是不连续的。如我们先前所述，PcG阻遏物结合INK4a启动子，但不结合ARF。在这里，我们确定了PcG结合的第二个峰位于INK4b启动子上游〜3 kb。在祖细胞分化和衰老过程中，PcG沉默子EZH2减弱，导致PRC结合丢失以及INK4b和INK4a的转录激活。基因座的表达模式由其在空间中的组织反映。在抑制状态下，PRC结合区非常接近，而中间带有ARF的染色质则循环。 EZH2的下调导致〜35 kb抑制性染色质环的释放以及INK4a和INK4b的诱导，而ARF表达保持不变。结论在多种生理过程中，PcG沉默子可以结合并协调INK4b和INK4a的表达，但不能与ARF结合。发育受调节的EZH2水平是可以确定INK4b-ARF-INK4a基因座的高级染色质结构和表达模式的因素之一，将人类祖细胞分化与增殖控制联系起来。我们的结果揭示了长距离控制的染色质循环机制，并反对涉及PcG沉默子在INK4b-ARF-INK4a基因座上均匀分布的模型。

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