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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.

EZH2-dependent chromatin looping controls INK4a and INK4b, but not ARF, during human progenitor cell differentiation and cellular senescence