DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat

The C9orf72 hexanucleotide repeat expansion (HRE) is the most frequent genetic cause of the neurodegen-erative 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 expres-sion, DAXX plays a key role in the suppression of basal and stress-inducible expression of C9orf72 via chro-matin remodeling and epigenetic modifications of the promoter of the major C9orf72 transcript. Downregu-lation 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.

Automated summary

The C9orf72 HRE DNA binds to DAXX and promotes its liquid-liquid phase separation, resulting in chromatin remodeling and epigenetic changes. DAXX regulates global gene expression and suppresses the expression of C9orf72 through chromatin remodeling and epigenetic modifications. Modulating DAXX or rebalancing epigenetic modifications can mitigate the stress-induced sensitivity of C9orf72-patient-derived motor neurons.