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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Deregulation of common genes by c-Myc and its direct target, MT-MC1
Kenneth R Rogulski1, Debra E Cohen, David L Corcoran
1Section of Hematology/Oncology, Children's Hospital of Pittsburgh, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA.
Abstract:
In addition to its role in cancer, the c-Myc oncoprotein controls many normal cellular processes as a consequence of its function as a basic helix-loop-helix leucine zipper transcription factor. Determining which of the myriad genes under c-Myc control are relevant for these various roles is thus a major challenge. mt-mc1 is a direct c-Myc target gene whose overexpression recapitulates multiple c-Myc phenotypes, including transformation. Using transcriptional profiling, we now show that MT-MC1-overexpressing myeloid cells misregulate a total of 47 distinct transcripts, a large proportion of which are involved in signal transduction and/or cancer. Analysis of these genes reveals a consensus promoter structure consisting of multiple, often closely spaced c-Myc binding sites and three additional Wilm's tumor and Egr1-like motifs. More than one-third of MT-MC1 target genes are also clustered on six cancer-associated chromosomal loci. Most surprisingly, all of the transcripts examined also are regulated by c-Myc. Finally, an estrogen receptor-MT-MC1 fusion protein was used to establish that all examined transcripts were regulated directly by the chimeric protein. Our results thus indicate that MT-MC1 target genes largely comprise a subset of those regulated by c-Myc. We propose that the properties imparted by MT-MC1 are the result of its control of a small and select c-Myc target gene population.
Insights
The oncogenic transcription factor c-Myc regulates many genes. A specific target, MT-MC1, controls a subset of these genes, impacting cell signaling and cancer development.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- The c-Myc oncoprotein, a transcription factor, regulates numerous cellular processes beyond cancer.
- Identifying specific c-Myc target genes responsible for its diverse cellular roles is a significant challenge.
Purpose of the Study:
- To investigate the downstream transcriptional targets of MT-MC1, a direct c-Myc target gene.
- To elucidate the functional significance of MT-MC1 in cellular processes and its relationship to c-Myc regulation.
Main Methods:
- Transcriptional profiling of myeloid cells overexpressing MT-MC1.
- Bioinformatic analysis of promoter regions for transcription factor binding sites.
- Chromosomal localization analysis of identified target genes.
- Functional validation using an estrogen receptor-MT-MC1 fusion protein.
Main Results:
- Overexpression of MT-MC1 in myeloid cells led to the misregulation of 47 distinct transcripts, many involved in signal transduction and cancer.
- A consensus promoter structure with multiple c-Myc binding sites and other motifs was identified in MT-MC1 target genes.
- Over one-third of MT-MC1 targets are located on cancer-associated chromosomal loci.
- All examined MT-MC1 target genes were also found to be regulated by c-Myc, with direct regulation confirmed by the fusion protein.
Conclusions:
- MT-MC1 target genes represent a distinct subset of genes directly regulated by c-Myc.
- MT-MC1 exerts its cellular effects, including transformation, through the control of this specific gene population.
- Understanding MT-MC1's regulatory network provides insights into c-Myc's broader functions in normal and cancerous cells.
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