Liu Y-T et al.
deletion or silencing is common across human cancer, reinforcing the general importance of bypassing its tumor suppression in cancer formation or progression. In rhabdomyosarcoma (RMS) and neuroblastoma, two common childhood cancers, the three transcripts are independently expressed to varying degrees, but one, is uniformly silenced. Although TGFÎ² induces certain transcripts in HeLa cells, it was unable to do so in five tested RMS lines unless the cells were pretreated with a broadly acting methyltransferase inhibitor, DZNep, or one targeting EZH2. induction by TGFÎ² correlated with de novo appearance of three H3K27Ac peaks within a 20â€‰kb element âˆ¼150â€‰kb proximal to . Deleting that segment prevented their induction by TGFÎ² but not a basal increase driven by methyltransferase inhibition alone. Expression of two transcripts was enhanced by dCas9/CRISPR activation targeting either the relevant promoter or the 20â€‰kb elements, and this "precise" manipulation diminished RMS cell propagation inÂ vitro. Our findings show crosstalk between methyltransferase inhibition and TGFÎ²-dependent activation of a remote enhancer to reverse silencing. Though focused on here, such crosstalk may apply to other TGFÎ²-responsive genes and perhaps govern this signaling protein's complex effects promoting or blocking cancer.