Interruption of aberrant chromatin looping is required for regenerating RB1 function and suppressing tumorigenesis

RB transcriptional corepressor 1 (RB1) is really a critical regulatory gene in physiological and pathological processes. Genetic mutation is regarded as the primary reason for RB1 inactivation. However, accumulating evidence has proven that does not all RB1 disorder is triggered by gene mutations, and also the additional mechanism underlying RB1 disorder remains unclear. Here, we first of all demonstrate that a CCCTC binding factor (CTCF) mediated intrachromosomal looping offered like a regulatory inducer to inactivate RB1. When the core genomic fragment was deleted by Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9), this intrachromosomal looping was disrupted. Following the open of chromatin, Enhancer of Zeste Homolog 2 (EZH2) was launched and decreased the amount of Tri-Methyl-Histone H3 Lys27 (H3K27me3) in the RB1 promoter, which substantially restored the expression of RB protein (pRB) and inhibited tumorigenesis. Additionally, targeted correction of abnormal RB1 looping while using small-molecule compound GSK503 efficiently restored RB1 transcription and covered up tumorigenesis. Our study reveals an alternate transcriptional mechanism underlying RB1 disorder separate from gene mutation, and evolving the invention of potential therapeutic chemicals according to aberrant chromatin looping.