DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat

Yang Liu, Zhiyuan Huang, Honghe Liu, Zhicheng Ji, Amit Arora, Danfeng Cai, Hongjin Wang, Mingming Liu, Eric A.J. Simko, Yanjun Zhang, Goran Periz, Zhe Liu, Jiou Wang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1205-1221.e9
Issue number8
StatePublished - Apr 19 2023


  • ALS
  • C9orf72
  • DAXX
  • DNA
  • FTD
  • chromatin
  • epigenetic
  • neurodegeneration
  • phase separation
  • transcription

ASJC Scopus subject areas

  • Neuroscience(all)


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