Related Experiment Video
Updated: May 9, 2026
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
DPY30 regulates pathways in cellular senescence through ID protein expression
Elisabeth Simboeck1, Arantxa Gutierrez, Luca Cozzuto
1Centre for Genomic Regulation (CRG) and UPF, Department of Gene Regulation, Stem Cells and Cancer, Barcelona, Spain.
Abstract:
Cellular senescence is an intrinsic defense mechanism to various cellular stresses: while still metabolically active, senescent cells stop dividing and enter a proliferation arrest. Here, we identify DPY30, a member of all mammalian histone H3K4 histone methyltransferases (HMTases), as a key regulator of the proliferation potential of human primary cells. Following depletion of DPY30, cells show a severe proliferation defect and display a senescent phenotype, including a flattened and enlarged morphology, elevated level of reactive oxygen species (ROS), increased SA-β-galactosidase activity, and formation of senescence-associated heterochromatin foci (SAHFs). While DPY30 depletion leads to a reduced level of H3K4me3-marked active chromatin, we observed a concomitant activation of CDK inhibitors, including p16INK4a, independent of H3K4me3. ChIP experiments show that key regulators of cell-cycle progression, including ID proteins, are under direct control of DPY30. Because ID proteins are negative regulators of the transcription factors ETS1/2, depletion of DPY30 leads to the transcriptional activation of p16INK4a by ETS1/2 and thus to a senescent-like phenotype. Ectoptic re-introduction of ID protein expression can partially rescue the senescence-like phenotype induced by DPY30 depletion. Thus, our data indicate that DPY30 controls proliferation by regulating ID proteins expression, which in turn lead to senescence bypass.
Insights
DPY30, a histone methyltransferase, is crucial for human cell proliferation. Its depletion triggers cellular senescence by activating cell-cycle inhibitors, revealing a new pathway for senescence bypass.
Area of Science:
- Cellular and Molecular Biology
- Epigenetics
- Cellular Senescence
Background:
- Cellular senescence is a state of irreversible cell cycle arrest, acting as a defense against cellular stress.
- Senescent cells remain metabolically active but lose proliferative capacity.
- Histone modifications play critical roles in regulating gene expression and cellular processes.
Purpose of the Study:
- To identify key regulators of proliferation potential in human primary cells.
- To elucidate the role of DPY30 in cellular senescence and proliferation.
- To understand the molecular mechanisms linking DPY30 to senescence.
Main Methods:
- Depletion of DPY30 using specific techniques.
- Assessment of cellular senescence markers (morphology, ROS, SA-β-gal, SAHFs).
- Chromatin immunoprecipitation (ChIP) to analyze histone modifications (H3K4me3) and protein binding.
- Analysis of cell-cycle inhibitors (p16INK4a) and transcription factors (ID proteins, ETS1/2).
Main Results:
- DPY30 depletion induced a severe proliferation defect and a senescent phenotype in human cells.
- DPY30 depletion reduced H3K4me3 levels but activated CDK inhibitors independently of H3K4me3.
- DPY30 directly regulates ID proteins, which control ETS1/2 activity, leading to p16INK4a activation and senescence.
- Restoring ID protein expression partially rescued the DPY30 depletion-induced senescence.
Conclusions:
- DPY30 is a critical regulator of human cell proliferation and senescence.
- The DPY30-ID protein-ETS1/2 pathway controls the expression of cell-cycle inhibitors, driving senescence.
- Targeting DPY30 or its downstream effectors may offer strategies for senescence bypass.
More Related Videos
Related Concept Videos
02:23Abnormal Proliferation
01:23Negative Regulator Molecules
02:15Replicative Cell Senescence
02:15Replicative Cell Senescence
01:31Regulation of the Unfolded Protein Response
01:31The Intrinsic Apoptotic Pathway