The Yin and Yang of Enhancer–Promoter Interactions

RESEARCH HIGHLIGHTS

Nature Reviews Molecular Cell Biology | Published online 20 Dec 2017; doi:10.1038/nrm.2017.136

GENE EXPRESSION in the promoters of two genes resulted in reduced YY1 binding, reduced contact frequency between the pro- The yin and yang of enhancer– moters and their cognate enhancers and, in one of the genes, reduced expression. The lack of reduced promoter interactions expression of one of the genes was probably due to YY1 binding at Transcription factors can facilitate the could bind to these elements and facil- other, less optimal motifs; indeed, physical interaction between enhanc- itate their interaction. They identified YY1 depletion resulted in decreased ers and promoters and looping of deletion of another zinc finger protein, YY1, expression of both genes. the intervening DNA between them. YY1 binding which, like CTCF, is essential for cell Next, using an inducible protein Such loops are formed within larger, viability and is ubiquitously expressed. degradation system, the genome-wide insulated chromosomal loops (also motifs… Importantly, co-immunoprecipitation effects of YY1 depletion were meas- known as topologically associating reduced of differentially tagged YY1 proteins ured. The expression of thousands domains (TADs)), which are formed contact confirmed that YY1 can form of genes was changed (increased or by dimerization of the zinc finger frequency homodimers. decreased), and in general the genes protein CTCF bound to chromatin. In various mouse and human cell with the greatest changes following Weintraub et al. now show that, anal- between the types, YY1 occupied enhancers and YY1 depletion were those with ogously to CTCF, the protein yin and promoters and promoters genome-wide. As expected promoters originally occupied by yang 1 (YY1) is a structural mediator their cognate from the cell-type specificity of YY1. HiChIP analysis showed that of enhancer–promoter looping enhancer function, YY1 enhancer interactions between YY1-occupied interactions. enhancers occupancy tended to be cell-type enhancers and promoters decreased CTCF does not generally bind specific. Using methods such as significantly after YY1 depletion. enhancers and promoters, so the HiChIP, which combine chromatin This was accompanied by changes in authors searched for proteins that immunoprecipitation with chro- the expression of the majority (60%) mosome conformation capture, the of genes that were connected by YY1 authors showed that YY1 mainly enhancer–promoter loops. associated with enhancer–promoter In summary, YY1 globally medi- interactions, including more complex ates enhancer–promoter interactions contacts between super-enhancer by binding to DNA and facilitating elements and their target promoters. the formation of chromatin loops, By contrast, the majority of CTCF- probably through its dimerzation. associated interactions connected This general function could account insulator elements, in agreement with for the variable reported functions their role in forming TADs. of YY1, which include both gene To examine whether YY1 could activation and gene repression. facilitate enhancer–promoter looping Eytan Zlotorynski interactions, YY1 was tested in an in vitro DNA circularization assay. ORIGINAL ARTICLE Weintraub, A.S. et al. YY1 is The addition of purified YY1, which a structural regulator of enhancer–promoter had DNA binding capacity, increased loops. Cell https://doi.org/10.1016/j. cell.2017.11.008 (2017) the rate of circularization, and this FURTHER READING Soutourina, J. Transcription depended on the presence of YY1 regulation by the Mediator complex. Nat. Rev. Mol. binding motifs in the DNA. In living Cell Biol. http://dx.doi.org/10.1038/nrm.2017.115 (2017) cells, deletion of YY1 binding motifs S. Bradbrook/Macmillan Publishers Limited