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MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity

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...

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Autores principales: Zheng, Jun-Yi, Wang, Chen-Yu, Gao, Chuan, Xiao, Qiong, Huang, Cheng-Wei, Wu, Min, Li, Lian-Yun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024252/
https://www.ncbi.nlm.nih.gov/pubmed/33824309
http://dx.doi.org/10.1038/s41419-021-03647-2
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author Zheng, Jun-Yi
Wang, Chen-Yu
Gao, Chuan
Xiao, Qiong
Huang, Cheng-Wei
Wu, Min
Li, Lian-Yun
author_facet Zheng, Jun-Yi
Wang, Chen-Yu
Gao, Chuan
Xiao, Qiong
Huang, Cheng-Wei
Wu, Min
Li, Lian-Yun
author_sort Zheng, Jun-Yi
collection PubMed
description 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.
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spelling pubmed-80242522021-04-21 MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity Zheng, Jun-Yi Wang, Chen-Yu Gao, Chuan Xiao, Qiong Huang, Cheng-Wei Wu, Min Li, Lian-Yun Cell Death Dis Article 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. Nature Publishing Group UK 2021-04-06 /pmc/articles/PMC8024252/ /pubmed/33824309 http://dx.doi.org/10.1038/s41419-021-03647-2 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zheng, Jun-Yi
Wang, Chen-Yu
Gao, Chuan
Xiao, Qiong
Huang, Cheng-Wei
Wu, Min
Li, Lian-Yun
MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
title MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
title_full MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
title_fullStr MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
title_full_unstemmed MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
title_short MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
title_sort mll3 suppresses tumorigenesis through regulating tns3 enhancer activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024252/
https://www.ncbi.nlm.nih.gov/pubmed/33824309
http://dx.doi.org/10.1038/s41419-021-03647-2
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