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SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
TGFβ-dependent gene expression shows that senescence correlates with abortive differentiation along several lineages
Judith Müller1, Birgit Samans, Jan van Riggelen
1Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
Abstract:
Deregulated expression of Myc under the control of an immunoglobulin enhancer induces lymphoma formation in mice. The development of lymphomas is limited by TGFβ-dependent senescence and high levels of Myc expression are continuously required to antagonize senescence. The biological processes underlying senescence are not fully resolved. We report here a comprehensive analysis of TGFβ-dependent alterations in gene expression when the Myc transgene is switched off. Our data show that Myc-induced target genes are downregulated in a TGFβ-independent manner. In contrast, TGFβ is required to upregulate a broad spectrum of genes that are characteristic of different T-cell lineages when Myc is turned off. The analysis reveals a significant overlap between these Myc-repressed genes with genes that are targets of polycomb repressive complexes in embryonic stem cells. Therefore, TGFβ-dependent senescence is associated with gene expression patterns indicative of abortive cellular differentiation along several lineages.
Insights
Turning off Myc expression in lymphoma-prone mice triggers TGFβ-dependent cellular differentiation, revealing insights into senescence and T-cell lineage development.
Area of Science:
- * Molecular biology
- * Cancer research
- * Immunology
Background:
- * Deregulated Myc expression drives lymphoma in mice.
- * Transforming growth factor beta (TGFβ)-dependent senescence limits lymphoma development.
- * Continuous high Myc levels are needed to counteract senescence.
Purpose of the Study:
- * To comprehensively analyze TGFβ-dependent gene expression changes after Myc transgene inactivation.
- * To elucidate the biological processes underlying TGFβ-dependent senescence.
Main Methods:
- * Gene expression profiling in mice with inducible Myc transgenes.
- * Analysis of TGFβ-dependent and -independent gene regulation.
- * Comparison of gene expression patterns with Polycomb repressive complex targets.
Main Results:
- * Myc-induced genes decrease independently of TGFβ upon Myc inactivation.
- * TGFβ upregulates T-cell lineage-specific genes when Myc is off.
- * Myc-repressed genes show overlap with Polycomb targets in stem cells.
Conclusions:
- * TGFβ-dependent senescence involves gene expression patterns of abortive cellular differentiation.
- * Myc inactivation leads to TGFβ-mediated upregulation of lineage-specific genes.
- * Findings link senescence, differentiation, and Polycomb regulation in lymphoma.
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Abnormal Proliferation
TGF - β Signaling Pathway
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