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Atypical GATA transcription factor TRPS1 represses gene expression by recruiting CHD4/NuRD(MTA2) and suppresses cell migration and invasion by repressing TP63 expression.

ABSTRACT: Transcriptional repressor GATA binding 1 (TRPS1), an atypical GATA transcription factor, functions as a transcriptional repressor and is also implicated in human cancers. However, the underlying mechanism of TRPS1 contributing to malignancy remains obscure. In the current study, we report that TRPS1 recognizes both gene proximal and distal transcription start site (TSS) sequences to repress gene expression. Co-IP mass spectrometry and biochemical studies showed that TRPS1 binds to CHD4/NuRD(MTA2). Genome-wide and molecular studies revealed that CHD4/NuRD(MTA2) is required for TRPS1 transcriptional repression. Mechanically, TRPS1 and CHD4/NuRD(MTA2) form precision-guided transcriptional repression machinery in which TRPS1 guides the machinery to specific target sites by recognizing GATA elements, and CHD4/NuRD(MTA2) represses the transcription of target genes. Furthermore, TP63 was identified and validated to be a direct target of TRPS1-CHD4/NuRD(MTA2) complex, which represses TP63 expression by involving decommission of TP63 enhancer in the described precision-guided manner, leading to a reduction of the ?Np63 level and contributing to migration and invasion of cancer cells.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6299095 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Project description:BackgroundsThe NuRD (Nucleosome Remodeling and Deacetylation) complex is a repressive complex in gene transcription by modulating chromatin accessibility of target genes to transcription factors and RNA polymerase II. Although individual subunits of the complex have been implicated in many other cancer types, the complex's role in human hepatocellular carcinoma (HCC) is not fully understood. More importantly, the NuRD complex has not yet been investigated as a whole in cancers.MethodsWe analyzed the expression of the NuRD complex in HCC and evaluated the prognostic value of NuRD complex expression in HCC using the RNA-seq data obtained from the TCGA project. We examined the effect of CHD4 knockdown on HCC cell proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition, colony-forming ability, and on complement gene expression. We also performed bioinformatic analyses to investigate the correlation between the NuRD complex expression and immune infiltration.ResultsWe found that nine subunits, out of 14 subunits of the NuRD complex examined, were significantly overexpressed in HCC, and their expression levels were positively correlated with cancer progression. More importantly, our data also demonstrated that these subunits tended to be overexpressed as a whole in HCC. Subsequent studies demonstrated that knockdown of CHD4 in HCC cells inhibits cell proliferation, migration, invasion, and colony-forming ability and promotes apoptosis of HCC cells, indicating that the CHD4/NuRD complex plays oncogenic roles in HCC. Further analysis revealed that the CHD4/NuRD complex regulates complement gene expression in HCC. Intriguingly, we found that the CHD4/NuRD complex expression was inversely correlated with CD8 T cell infiltration in HCC.ConclusionsOur data demonstrate that the CHD4/NuRD complex plays an oncogenic role in human HCC and regulates complement gene expression in HCC cells. The results of inverse correlation between the CHD4/NuRD complex and CD8 T cell and DC cell infiltration in HCC suggest that the CHD4/NuRD complex not only plays direct regulatory roles in HCC cells, but also has an impact on the immune microenvironment of HCC.

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Atypical GATA transcription factor TRPS1 represses gene expression by recruiting CHD4/NuRD(MTA2) and suppresses cell migration and invasion by repressing TP63 expression.

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