Chromatin and Poly ADP-Ribosylation Dynamics in Human Aging

Aging is accompanied by widespread epigenetic reprogramming, including the loss of heterochromatin and altered chromatin-associated processes. These changes compromise transcriptional precision and genome stability. In this talk, I will explore the interplay between chromatin structure and poly-ADP ribosylation (PARylation) as a regulatory mechanism in both physiological and premature aging conditions. Using Cockayne Syndrome (CS) as a model of accelerated aging, we demonstrate that CSB-deficient cells exhibit chromatin decompaction, increased PARylation near transcription start sites, and mitochondrial dysfunction. Our studies show that restoring the heterochromatin mark alleviates PAR pathology and improves mitochondrial homeostasis. Additionally, we uncover a novel role of mitochondrial PARP and mitochondrial nucleoid PARylation in regulating mtDNA transcription, suggesting a cross-compartmental NAD⁺-dependent epigenetic signaling axis. These findings provide insight into how chromatin dynamics and PARylation shape aging phenotypes and offer potential avenues for therapeutic intervention in aging-related diseases.

Learning Objectives: 

1. Understand the relationship between chromatin structure and transcriptional integrity during aging.

2. Recognize the pathological role of PARylation in premature aging disorders like Cockayne Syndrome.