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Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles.

ABSTRACT: In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.

SUBMITTER: Walz S

PROVIDER: S-EPMC6879323 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles.

Walz Susanne S Lorenzin Francesca F Morton Jennifer J Wiese Katrin E KE von Eyss Björn B Herold Steffi S Rycak Lukas L Dumay-Odelot Hélène H Karim Saadia S Bartkuhn Marek M Roels Frederik F Wüstefeld Torsten T Fischer Matthias M Teichmann Martin M Zender Lars L Wei Chia-Lin CL Sansom Owen O Wolf Elmar E Eilers Martin M

Nature 20140709 7510

In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour ...[more]

PMID: 25043018

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Project description:BackgroundSesame (Sesamum indicum) can accumulate over 60% oil in its seed. However, low oil content genotypes with an oil content of less than 50% are also observed. To gain insights into how genes shape this variation, we examined 22 seed and carpel transcriptomes from 3 varieties of sesame with high and low oil content.ResultsA total of 34.6~52.2% of the sesame genes were expressed with a RPKM greater than 5 in the 22 tissue samples. The expressed gene numbers tended to decrease in the seed but fluctuated in the carpels from 10 to 30 days post-anthesis (DPA). Compared with that of the low oil content sesames, the high oil content sesame exhibited more positive gene expression during seed development. Typically, genes involved in lipid biosynthesis were enriched and could distinguish the high and low genotypes at 30 DPA, suggesting the pivotal role of seed oil biosynthesis in the later stages. Key homologous lipid genes that function in TAG biosynthesis, including those that encoded glycerol-3-phosphate acyltransferase (GPAT), acyl-CoA:diacylglycerol acyltransferase (DGAT), and phospholipid:diacylglycerol acyltransferase (PDAT), were strengthened asynchronously at different stages, but the lipid transfer protein (LTP)-encoding genes, including SIN_1019175, SIN_1019172 and SIN_1010009, usually were highlighted in the high oil content sesames. Furthermore, a list of 23 candidate genes was identified and predicted to be beneficial for higher oil content accumulation. Despite the different gene expression patterns between the seeds and carpels, the two tissues showed a cooperative relationship during seed development, and biological processes, such as transport, catabolic process and small molecule metabolic process, changed synchronously.ConclusionsThe study elucidated the different expression profiles in high and low oil content sesames and revealed key stages and a list of candidate genes that shaped oil content variation. These findings will accelerate dissection of the genetic mechanism of sesame oil biosynthesis.

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Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles.

Publications

Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles.

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