MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity.

Jun-Yi Zheng, Chen-Yu Wang, Chuan Gao, Qiong Xiao, Cheng-Wei Huang, Min Wu, Lian-Yun Li

Cell death & disease 2021 Apr 06

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MLL3 is a histone H3K4 methyltransferase that is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 depletion by CRISPR/sgRNA significantly enhanced cell migration, but did not elevate the proliferation rate of cancer cells. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused downregulation of H3K4me1 and H3K27ac on an enhancer ~ 7 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter and repression of enhancer activity by dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.

Citation

Jun-Yi Zheng, Chen-Yu Wang, Chuan Gao, Qiong Xiao, Cheng-Wei Huang, Min Wu, Lian-Yun Li. MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity. Cell death & disease. 2021 Apr 06;12(4):364