@article{de359ae7b2114a4e933c817633fd276e,
title = "DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat",
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",
author = "Yang Liu and Zhiyuan Huang and Honghe Liu and Zhicheng Ji and Amit Arora and Danfeng Cai and Hongjin Wang and Mingming Liu and Simko, {Eric A.J.} and Yanjun Zhang and Goran Periz and Zhe Liu and Jiou Wang",
note = "Funding Information: This work was supported by grants from NIH ( NS089616 , NS110098 , NS074324 , and NS128494 ), Packard Center for ALS Research at Johns Hopkins, Target ALS Foundation , Maryland Stem Cell Research Fund , and the U.S. Department of Defense . Bioinformatic analysis in this work was performed at the Advanced Research Computing at Hopkins (ARCH) core facility ( rockfish.jhu.edu ), which is supported by the National Science Foundation (NSF) grant number OAC1920103 . We would like to thank Justin Ichida at the University of Southern California for providing iPSC lines, NINDS and NIGMS Cell Repository, Ian Robey at the VA Biorepository Brain Bank (VA merit review BX002466 ), Lyle Ostrow, Kathleen Wilsbach, and Kathyrn Gallo at the Johns Hopkins ALS Postmortem Tissue Core, and the Target ALS Multicenter Postmortem Tissue Core for providing patient cells and tissues, Howard Hughes Medical Institute for the ATAC-PALM facility, and the members of Wang lab for discussion. Funding Information: This work was supported by grants from NIH (NS089616, NS110098, NS074324, and NS128494), Packard Center for ALS Research at Johns Hopkins, Target ALS Foundation, Maryland Stem Cell Research Fund, and the U.S. Department of Defense. Bioinformatic analysis in this work was performed at the Advanced Research Computing at Hopkins (ARCH) core facility (rockfish.jhu.edu), which is supported by the National Science Foundation (NSF) grant number OAC1920103. We would like to thank Justin Ichida at the University of Southern California for providing iPSC lines, NINDS and NIGMS Cell Repository, Ian Robey at the VA Biorepository Brain Bank (VA merit review BX002466), Lyle Ostrow, Kathleen Wilsbach, and Kathyrn Gallo at the Johns Hopkins ALS Postmortem Tissue Core, and the Target ALS Multicenter Postmortem Tissue Core for providing patient cells and tissues, Howard Hughes Medical Institute for the ATAC-PALM facility, and the members of Wang lab for discussion. Y.L. performed and analyzed most of the experiments. Z.H. helped with motor neuron differentiation and data collection. H.L. conducted the ATAC-seq experiments. Z.J. analyzed the HiChIP data. A.A. contributed to the SILAC-MS analysis. D.C. and Z.L. performed and analyzed the 2D ATAC-PALM experiments. H.W. and M.L. contributed to the bioinformatic analysis. E.S. contributed to the promoter analysis. Y.Z. performed the nascent RNA analysis. G.P. contributed to the molecular cloning and helped with manuscript preparation. Y.L. and J.W. designed the studies and wrote the paper with inputs from other authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = apr,
day = "19",
doi = "10.1016/j.neuron.2023.01.022",
language = "English (US)",
volume = "111",
pages = "1205--1221.e9",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "8",
}