DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat.

The C9orf72 hexanucleotide repeat expansion (HRE) is the most frequent genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we describe the pathogenic cascades that are initiated by the C9orf72 HRE DNA. The HRE DNA binds to its protein partner DAXX and promotes its liquid-liquid phase separation, which is capable of reorganizing genomic structures. An HRE-dependent nuclear accumulation of DAXX drives chromatin remodeling and epigenetic changes such as histone hypermethylation and hypoacetylation in patient cells. While regulating global gene expression, DAXX plays a key role in the suppression of basal and stress-inducible expression of C9orf72 via chromatin remodeling and epigenetic modifications of the promoter of the major C9orf72 transcript. Downregulation of DAXX or rebalancing the epigenetic modifications mitigates the stress-induced sensitivity of C9orf72-patient-derived motor neurons. These studies reveal a C9orf72 HRE DNA-dependent regulatory mechanism for both local and genomic architectural changes in the relevant diseases. [Display omitted] • G4C2 repeat DNA binds to DAXX and promotes its condensation and nuclear enrichment • LLPS of DAXX reprograms chromatin structures at the C9orf72 locus and in the genome • DAXX suppresses stress-related C9orf72 induction and changes global gene expression • Rebalancing DAXX alleviates stress-induced toxicity in C9orf72 HRE motor neurons This study has revealed pathogenic cascades initiated by C9orf72 hexanucleotide repeat DNA that influence genomic structures and gene expression. DAXX, a G4C2 repeat DNA-binding protein, regulates stress-dependent C9orf72 induction and global gene expression through chromatin remodeling and epigenetic changes as a key player mediating C9orf72 haploinsufficiency and DNA-dependent gain-of-function toxicities. [ABSTRACT FROM AUTHOR]