Investigating the Role of DNA Damage-induced Cytoplasmic DNA in Ataxia Telangiectasia

Abstract

Ataxia Telangiectasia (A-T) is a neurodegenerative disorder caused by loss-of-function mutations in the ATM gene, leading to impaired DNA damage response, genome instability, and progressive cerebellar degeneration. While previous studies have shown that unresolved DNA damage can trigger the export of chromatin fragments into the cytoplasm as cytoplasmic DNA (cytoDNA), which activates the cGAS-STING pathway and promotes inflammation, the in vivo relevance and broader molecular consequences of this process remain unclear. In this study, I investigated the consequences of DNA damage-induced cytoDNA accumulation in Atm^tm1Bal mice, focusing on transcriptomic changes and alterations in chromatin architecture.

I confirmed the accumulation of cytoDNA in the cerebellum of 2-month-old Atm^tm1Bal mice. RNA-Seq analysis revealed subtle but significant downregulation of genes such as Bcl5, Sema7a, Kbtbd11, Ireb2, and Insyn1, which are implicated in brain cell function and survival.

To explore chromatin architecture, I performed Hi-C analysis on Atm^tm1Bal and wild-type cerebella. Chromatin loop analysis revealed Atm^tm1Bal-specific promoter-enhancer loops at stress-responsive and DNA repair genes, including Polb and Sesn2, suggesting ATM loss may induce rewiring of regulatory interactions at key loci.

Building on our prior findings, I also assessed the role of cGAS in cytoDNA export. However, cGAS ChIP-seq and CUT&Tag showed minimal enrichment of specific binding sites, warranting further investigation.

Collectively, these findings show that unresolved DNA damage in ATM-mutant cerebellum leads to cytoDNA accumulation, transcriptional repression, and the formation of new chromatin loops. The emergence of regulatory loops might indicate a primed chromatin state preceding overt inflammation. This study offers mechanistic insight into how genome instability reshapes nuclear architecture and lays the foundation for understanding early events driving neuroinflammation in A-T and related disorders.

Date of Award	2025
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Danny Chi Yeu LEUNG (Supervisor)