research HIGHLIGHTS

GENETICS Could these enhancer proximities be linked to ongoing MYC trans­ cription and differences in nuclear One foot in the door: gene gating export of nascent MYC transcripts? RNA-​FISH analyses revealed two supports nuclear export of MYC mRNA dominant populations of active MYC alleles, which overlapped with The tethering of genes to nuclear colon epithelial cells (HCECs) and the respective location of enhancer pores can facilitate reactivation human colon cancer (HCT116) proximities. Importantly, relatively OSE-​mediated and rapid nuclear export of trans­ cells. This analysis showed that higher levels of transcriptionally cripts, a principle referred to as NUP153 binding was enriched in anchoring of active MYC alleles overlapped with gene gating. Gene gating has been many of the most highly connected MYC–OSE proximity signals in the MYC to the described in yeast and flies, but its enhancer regions within the two nuclear periphery compared with contribution to gene regulation topologically associating domains those overlapping with EnhD–MYC in human cells and to cancer is flanking MYC in both HCECs and is required proximity signals. unknown. Now, Scholz et al. show HCT116 cells. However, it was not for MYC Analysis of RNA isolated from that gene gating of transcriptionally enriched in constitutive lamina-​ nuclear or cytosolic fractions transcripts to active MYC alleles occurs in human associated domains of peripheral from HCT116 cells and HCECs escape from colon cancer cells and increases in either cell subjected to a 5-ethynyl uridine nuclear export and overall expression line. By contrast, in the oncogenic nuclear decay pulse–chase to determine nascent of MYC transcripts. super-​enhancer (OSE) region that MYC transcripts showed that the To start with, the researchers showed the highest degree of MYC ratio of cytoplasmic to nuclear constructed networks of interaction, NUP133 binding was MYC transcripts was higher in that impact human MYC based enriched specifically in HCT116 HCT116 cells than in HCECs. When on reads generated using the cells, whereas the MYC promoter inhibiting transcriptional elongation, Nodewalk technique, a chromosome region in HCT116 cells, and the nuclear MYC transcripts decayed conformation capture-​based assay to respective OSE and promoter regions at a higher rate than cytoplasmic investigate chromatin interactions. in HCECs, showed little or no transcripts and at similar rates To determine the relationship NUP133 binding. between HCT116 cells and HCECs. of these networks to nuclear pores, Next, the authors explored how It is known that WNT regulates these analyses were combined the NUP133 and OSE interaction MYC-​specific enhancers via TCF4, with genome-​wide binding data relates to nuclear architecture, using and disruption of β-​catenin and of 153 (NUP153) and chromatin in situ proximity (ChrISP) TCF4 complexes by the drug BC21 NUP133 (both of which are part of assays. ChrISP enables high-​resolution, reduced the interaction between the nuclear pore) in normal human fluorescence-​based detection of NUP133 and OSE in HCT116 cells. <16 nm physical proximity of NUP133 BC21 reduced the export rate of and digoxygenin-​labelled DNA nascent MYC transcripts and reduced fluorescence in situ hybridization total cytosolic MYC transcript levels (FISH) probes. HCT116 cells showed in HCT116 cells, showing that the higher NUP133–OSE proximity OSE-​mediated anchoring of MYC signals than HCECs. Moreover, to the nuclear pore is required for NUP133–OSE proximity signals MYC transcripts to escape from in HCT116 cells were higher at nuclear decay. the than in other This study highlights how nuclear intranuclear regions, indicating architecture can promote oncogenic a transient anchoring of OSE to gene expression. Whether this nuclear pores. Analyses of MYC– mechanism is involved in promoting OSE proximities in HCT116 tumour growth in vivo and in cells revealed that MYC–OSE other models of cancer remains proximity signals were highest to be shown. in the nuclear periphery. By contrast, the proximities of MYC to a MYC Ulrike Harjes

enhancer region, EnhD, which is Original article Scholz, B. A. et al. WNT more proximal to MYC and does signaling and AHCTF1 promote oncogenic MYC not bind NUP153 or NUP133, were expression through super-enhancer-mediated​ gene gating. Nat. Genet. 51, 1723–1731 (2019)

Credit: NKuvshinov/Alamy Stock Vector Stock NKuvshinov/Alamy Credit: lowest in the nuclear periphery.

NAtuRe Reviews | CANceR volume 20 | FEBRUARY 2020 | 71