Centromere inactivation during aging can be rescued in human cells

Area of Science:

• Cellular senescence
• Epigenetics
• Molecular biology

Background:

• Aging is characterized by genetic, epigenetic, and physiological changes, including loss of heterochromatin and reduced histone levels.
• Centromeres, crucial for chromosome segregation, are affected during cellular aging.
• The centromeric histone H3 variant CENP-A plays a vital role in centromere function.

Purpose of the Study:

• To investigate the fate of centromeres during human cellular aging.
• To elucidate the mechanisms underlying centromeric dysfunction in aged cells.
• To explore strategies for mitigating age-related centromere inactivation.

Main Methods:

• Tracking centromere dynamics in aging human cells.
• Assessing CENP-A levels and p53-dependent regulation.
• Investigating epigenetic mechanisms involving lysine-specific demethylase 1 (LSD1/KDM1A) at centromeres.
• Evaluating the effects of dual inhibition of p53 and LSD1/KDM1A.

Main Results:

• CENP-A is downregulated in aged cells in a p53-dependent manner.
• Epigenetic repression of centromeric noncoding transcription via LSD1/KDM1A recruitment inhibits de novo CENP-A loading.
• Dual inhibition of p53 and LSD1/KDM1A restores centromeric protein levels and transcripts.
• Mitotic rejuvenation of aged cells is achieved through this dual inhibition.

Conclusions:

• Aging leads to centromeric inactivation through a novel epigenetic mechanism involving p53 and LSD1/KDM1A.
• This mechanism suppresses CENP-A loading and centromeric transcription.
• Targeting p53 and LSD1/KDM1A offers a potential strategy to reactivate centromeres and rejuvenate aged cells.