Evidence map›Paper›PMID 36822200›Full record

ArticleNeuron2023

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 and 3 more

Erratum issuedOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuron, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
4.3field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 21 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Wild-typemedRxiv : the preprint server for health sciences · 2026
    Article
  5. Review
  6. Epigenetics in Neurodegenerative Diseases.Sub-cellular biochemistry · 2025
    Review
  7. NAR molecular medicine · 2024
    Article
  8. Article
  9. Review
  10. Review
  11. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 1 country.

Yang LiuDepartment 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.
Zhiyuan HuangDepartment 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.
Honghe LiuDepartment 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.
Zhicheng JiDepartment of Biostatistics and Bioinformatics, Duke University School of Medicine, Duke University, Durham, NC 27710, USA.
Amit AroraDepartment 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.
Danfeng CaiDepartment 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.
Hongjin WangDepartment 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.
Mingming LiuDepartment 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.
Eric A J SimkoDepartment 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.
Yanjun ZhangDepartment 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.
Goran PerizDepartment 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.
Zhe LiuJanelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
Jiou WangDepartment 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.
Johns Hopkins University · USHoward Hughes Medical Institute · USDuke University · US

Funding

Neurodegeneration and Proteotoxicity Dissected in C. elegans and MammalsR01NS074324 · NINDS · JOHNS HOPKINS UNIVERSITY · PI WANG, JIOU · 2011 to 2025
$6.2M
Investigating the role of C9orf72 in autophagic and metabolic dysregulation in ALS/FTDR01NS089616 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Jiou Wang · 2015 to 2026
$6.0M
Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2R01NS110098 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Jiou Wang · 2019 to 2026
$5.0M
Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat ExpansionR01NS128494 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Jiou Wang · 2022 to 2026
$3.1M
Probing the Formation and Function of Transcription Hubs-Equipment SupplementR35GM142837 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI CAI, DANFENG · 2021 to 2025
$2.4M
BLRD VA I01 BX002466NIGMS NIH HHS R35 GM142837NINDS NIH HHS R01 NS074324NINDS NIH HHS R01 NS089616NINDS NIH HHS R01 NS110098NINDS NIH HHS R01 NS128494
6 · The paper itself

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.

Indexed as

Amyotrophic Lateral SclerosisC9orf72 ProteinFrontotemporal DementiaDNADNA Repeat ExpansionEpigenesis, GeneticHistonesHumansC9orf72 ProteinC9orf72 protein, humanDNAHistonesALSC9orf72chromatinDAXXDNAepigeneticFTDneurodegenerationphase separationtranscription

Identifiers

PMID36822200
PMCPMC10121948
OpenAlexW4321491228

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.