Chromosomal instability-associated MAT1 lncRNA insulates MLL1-guided histone methylation and accelerates tumorigenesis

Acquired chromosomal instability, especially copy number variations (CNVs), has been considered an important determinant of cancer progression and clinical survival. However, the functional role of aberrant CNV-induced lncRNAs in tumorigenesis remains unexplored. Here, we identify a CNV-induced MSC-antisense-transcript 1 (MAT1) lncRNA that plays an oncogenic role in promoting tumorigenesis of uveal melanoma in orthotopic and metastatic xenografts. In addition, our data suggest that MAT1 interrupts the interaction between the MLL1 complex and the PCDH20 promoter by forming an RNA-DNA triplex structure, subsequently abolishing H3K4 trimethylation and inactivating transcription of tumor suppressor PCDH20 to accelerate tumorigenesis. Our data show an intriguing insulation pattern of H3K4 histone modification in tumorigenesis mediated by a lncRNA, thereby providing an alternative mechanism for noncoding blockers in gene regulation. [Display omitted] •A CNV-induced MAT1 lncRNA plays an oncogenic role in tumorigenesis of uveal melanoma•MAT1 interrupts the interaction of MLL1 and PCDH20 promoter by forming triplex structure•An intriguing lncRNA-mediated insulation pattern of H3K4 histone modification in tumors Pan et al. demonstrate a lncRNA-insulating mechanism in which a CNV-induced lncRNA MAT1 serves as a blocker to interrupt the interaction between the MLL protein complex and the promoter of tumor suppressor PCDH20 by forming an RNA-DNA triplex structure, thereby abolishing H3K4 trimethylation and accelerating UM tumorigenesis.