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

doi:10.1016/j.neuron.2023.01.022

DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat

Neuron. 2023 Apr 19;111(8):1205-1221.e9. doi: 10.1016/j.neuron.2023.01.022. Epub 2023 Feb 22.

Authors

Yang Liu¹, Zhiyuan Huang¹, Honghe Liu¹, Zhicheng Ji², Amit Arora¹, Danfeng Cai³, Hongjin Wang¹, Mingming Liu¹, Eric A J Simko¹, Yanjun Zhang¹, Goran Periz¹, Zhe Liu⁴, Jiou Wang⁵

Affiliations

¹ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
² Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Duke University, Durham, NC 27710, USA.
³ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Department of Biophysics and Biophysical Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
⁵ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: jiouw@jhmi.edu.

Abstract

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.

Keywords: ALS; C9orf72; DAXX; DNA; FTD; chromatin; epigenetic; neurodegeneration; phase separation; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / pathology
C9orf72 Protein* / genetics
C9orf72 Protein* / metabolism
DNA / genetics
DNA / metabolism
DNA Repeat Expansion / genetics
Epigenesis, Genetic
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / pathology
Histones / metabolism
Humans

Substances

C9orf72 Protein
C9orf72 protein, human
DNA
Histones

Abstract

Publication types

MeSH terms

Substances

Grants and funding