Generation of onco-enhancer enhances chromosomal remodeling and accelerates tumorigenesis

Abstract

Chromatin remodeling impacts the structural neighborhoods and regulates gene expression. However, the role of enhancer-guided chromatin remodeling in the gene regulation remains unclear. Here, using RNA-seq and ChIP-seq, we identified for the first time that neurotensin (NTS) serves as a key oncogene in uveal melanoma and that CTCF interacts with the upstream enhancer of NTS and orchestrates an 800 kb chromosomal loop between the promoter and enhancer. Intriguingly, this novel CTCF-guided chromatin loop was ubiquitous in a cohort of tumor patients. In addition, a disruption in this chromosomal interaction prevented the histone acetyltransferase EP300 from embedding in the promoter of NTS and resulted in NTS silencing. Most importantly, in vitro and in vivo experiments showed that the ability of tumor formation was significantly suppressed via deletion of the enhancer by CRISPR-Cas9. These studies delineate a novel onco-enhancer guided epigenetic mechanism and provide a promising therapeutic concept for disease therapy.

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

“…Effective targeted correction of these abnormal chromatin loops is an open question and a research hotspot. Most current studies focus on deleting abnormal genomic fragments or ectopically expressing foreign factors 38 ; however, these classic experimental technologies in the laboratory have obvious limitations for further industrial application. Finding suitable leading small-molecule compounds for chromatin correction is an efficient and promising way to overcome these barriers 6 .…”

Genome Editing Approaches with CRISPR/Cas9 for Cancer Treatment: Critical Appraisal of Preclinical and Clinical Utility, Challenges, and Future Research

“…In addition, many lncRNAs are positioned in proximity of coding regions, and collateral, unwanted damage can occur. A recently published protocol describes a simple and effective method to produce genomic knockouts of lncRNAs [ 73 ] Trans-acting elements of oncogene expression regulation are among the listed CRISPR/Cas9 targets, such as the case of CCCTC-binding factor ( CTCF ), that creates a loop between the neurotensin ( NTS ) oncogene and an upstream enhancer sequence, promoting an NTS overexpression in uveal melanoma tumor cells [ 74 ]. It is worth mentioning a particular study [ 75 ], in which the authors switched their search for potential CRISPR/Cas9 targets from oncogenes or other sequences with an oncogenic role, to a widespread class of repeat sequences through the human genome, namely the Alu short interspersed nuclear elements (SINE) class of retrotransposons, that number approximately 3 million conserved copies in our genome [ 76 ].…”

Topologically Associating Domains and Regulatory Landscapes in Development, Evolution and Disease

“…Indeed, the disruption of boundaries demarcating insulated neighborhoods, which are chromatin domains smaller in size than TADs, leads to aberrant activation of proto-oncogenes, such as TAL1 and LMO2 associated with T-cell acute lymphoblastic leukemia ( Hnisz et al, 2016 ). In the opposite situation, the overexpression of the Neurotensin gene NTS , a central nervous system neurotransmitter, has been recently related with melanomas due to a gained CTCF-mediated chromatin loop that establish contacts between the NTS promoter and a CRE in the intron of the LRRIQ1 gene located 800 Kb away ( Chai et al, 2021 ).…”