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Published on: December 16, 2016
Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus
Alexandros Tzatsos1, Raymond Pfau, Sotirios C Kampranis
1Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Abstract:
The histone H3 demethylase Not dead yet-1 (Ndy1/KDM2B) is a physiological inhibitor of senescence. Here, we show that Ndy1 is down-regulated during senescence in mouse embryonic fibroblasts (MEFs) and that it represses the Ink4a/Arf locus. Ndy1 counteracts the senescence-associated down-regulation of Ezh2, a component of polycomb-repressive complex (PRC) 2, via a JmjC domain-dependent process leading to the global and Ink4a/Arf locus-specific up-regulation of histone H3K27 trimethylation. The latter promotes the Ink4a/Arf locus-specific binding of Bmi1, a component of PRC1. Ndy1, which interacts with Ezh2, also binds the Ink4a/Arf locus and demethylates the locus-associated histone H3K36me2 and histone H3K4me3. The combination of histone modifications driven by Ndy1 interferes with the binding of RNA Polymerase II, resulting in the transcriptional silencing of the Ink4a/Arf locus and contributing to the Ndy1 immortalization phenotype. Other studies show that, in addition to inhibiting replicative senescence, Ndy1 inhibits Ras oncogene-induced senescence via a similar molecular mechanism.
Insights
The histone demethylase Ndy1 (KDM2B) inhibits senescence by repressing the Ink4a/Arf locus. It achieves this through epigenetic modifications, preventing cellular aging and promoting an immortalization phenotype.
Area of Science:
- Epigenetics
- Cellular senescence
- Gene regulation
Background:
- The histone H3 demethylase Not dead yet-1 (Ndy1/KDM2B) is identified as a physiological inhibitor of senescence.
- Senescence is a cellular process that can be triggered by various stressors, including oncogene activation and replicative exhaustion.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Ndy1 inhibits senescence.
- To investigate the role of Ndy1 in regulating the Ink4a/Arf locus during senescence.
Main Methods:
- Analysis of Ndy1 expression during senescence in mouse embryonic fibroblasts (MEFs).
- Chromatin immunoprecipitation (ChIP) assays to assess histone modifications and protein binding at the Ink4a/Arf locus.
- Biochemical assays to determine Ndy1's demethylase activity and interactions with other proteins.
Main Results:
- Ndy1 expression is down-regulated during senescence and represses the Ink4a/Arf locus.
- Ndy1 counteracts Ezh2 down-regulation, increasing H3K27 trimethylation and promoting Bmi1 binding to the Ink4a/Arf locus.
- Ndy1 demethylates H3K36me2 and H3K4me3 at the Ink4a/Arf locus, interfering with RNA Polymerase II binding and leading to transcriptional silencing.
- Ndy1 inhibits both replicative and Ras oncogene-induced senescence through similar mechanisms.
Conclusions:
- Ndy1 functions as a key epigenetic regulator that suppresses cellular senescence.
- Ndy1's ability to maintain an epigenetic state that silences the Ink4a/Arf locus contributes to cellular immortalization.
- Ndy1's inhibitory role in senescence is conserved across different senescence-inducing pathways.
