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A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells.

ABSTRACT: Overexpression of c-Myc is one of the most common alterations in human cancers, yet it is not clear how this transcription factor acts to promote malignant transformation. To understand the molecular targets of c-Myc function, we have used an unbiased genome-wide location-analysis approach to examine the genomic binding sites of c-Myc in Burkitt's lymphoma cells. We find that c-Myc together with its heterodimeric partner, Max, occupy >15% of gene promoters tested in these cancer cells. The DNA binding of c-Myc and Max correlates extensively with gene expression throughout the genome, a hallmark attribute of general transcription factors. The c-Myc/Max heterodimer complexes also colocalize with transcription factor IID in these cells, further supporting a general role for overexpressed c-Myc in global gene regulation. In addition, transcription of a majority of c-Myc target genes exhibits changes correlated with levels of c-myc mRNA in a diverse set of tissues and cell lines, supporting the conclusion that c-Myc regulates them. Taken together, these results suggest a general role for overexpressed c-Myc in global transcriptional regulation in some cancer cells and point toward molecular mechanisms for c-Myc function in malignant transformation.

SUBMITTER: Li Z

PROVIDER: S-EPMC166200 | biostudies-literature | 2003 Jul

REPOSITORIES: biostudies-literature

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A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells.

Li Zirong Z Van Calcar Sara S Qu Chunxu C Cavenee Webster K WK Zhang Michael Q MQ Ren Bing B

Proceedings of the National Academy of Sciences of the United States of America 20030613 14

Overexpression of c-Myc is one of the most common alterations in human cancers, yet it is not clear how this transcription factor acts to promote malignant transformation. To understand the molecular targets of c-Myc function, we have used an unbiased genome-wide location-analysis approach to examine the genomic binding sites of c-Myc in Burkitt's lymphoma cells. We find that c-Myc together with its heterodimeric partner, Max, occupy >15% of gene promoters tested in these cancer cells. The DNA b ...[more]

PMID: 12808131

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Project description:Background: MYC is a transcription factor encoded by the c-MYC gene (thereafter termed MYC). MYC is key transcription factor involved in many central cellular processes including ribosomal biogenesis. MYC is overexpressed in the majority of human tumours including aggressive B-cell lymphoma especially Burkitt's lymphoma. Although Burkitt's lymphoma is a highlight example for MYC overexpression due to a chromosomal translocation, no global analysis of MYC binding sites by chromatin immunoprecipitation (ChIP) followed by global next generation sequencing (ChIP-Seq) has been conducted so far in Burkitt's lymphoma. Methodology/Principal Findings: ChIP-Seq was performed with a MYC-specific antibody giving rise to 7,054 predicted MYC binding sites after bioinformatics analysis of a total of 19 million sequence reads. In line with previous findings, binding sites accumulate in gene sets known to be involved in the ribosomal biogenesis, histone acetyltransferase and methyltransferase complexes and the cell cycle demonstrating a regulatory role of MYC in these processes. Unexpectedly, MYC binding sites also accumulate in genes typically expressed in mature B-cells. To assess the functional consequences of altered MYC binding, the ChIP-Seq data were supplemented with siRNA mediated knock-downs of MYC in BL cell lines followed by gene expression profiling. Interestingly, amongst others, genes involved in B-cell function were up-regulated in response to MYC silencing. Conclusion/Significance: The 7,054 MYC-binding sites identified by our ChIP-Seq approach greatly extend the knowledge regarding MYC binding in Burkitt's lymphoma and sheds further light on the enormous complexity of the MYC regulatory network. Especially our observation that (i) many B-cell relevant genes are targeted by MYC and (ii) that MYC down-regulation leads to an up-regulation of B-cell genes highlights an interesting aspect of BurkittM-BM-4s lymphoma biology. [ChIP-Seq] Analysis of MYC DNA binding sites by ChiP-Seq in 5 BurkittM-BM-4s lymphoma cell lines (Raji, Ramos, Blue1, BL41, CA46) [mRNA expression profiling] siRNA-mediated knock-down of MYC was done employing the BL cell lines Raji, BL41 and Blue1 in order to detect MYC-driven gene expression changes. For this purpose, the cells were Amaxa-transfected using MYC smart pool siRNA and control siRNA (Thermo Scientific/Dharmacon, Erembodegem, Belgium), respectively.

Dataset Information

A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells.

Publications

A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells.

Similar Datasets

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