Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls

Stanislav Tsitkov, Kelsey Valentine, Velina Kozareva, Aneesh Donde, Aaron Frank, Susan Lei, Jennifer Eyk, Steve Finkbeiner, Jeffrey D. Rothstein, Leslie M. Thompson, Dhruv Sareen, Clive N. Svendsen and Ernest Fraenkel ()
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Stanislav Tsitkov: Massachusetts Institute of Technology
Kelsey Valentine: Massachusetts Institute of Technology
Velina Kozareva: Massachusetts Institute of Technology
Aneesh Donde: Massachusetts Institute of Technology
Aaron Frank: Cedars-Sinai Medical Center
Susan Lei: Cedars-Sinai Medical Center
Jennifer Eyk: Smidt Heart Institute, Cedars-Sinai Medical Center
Steve Finkbeiner: Center for Systems and Therapeutics, Gladstone Institutes
Jeffrey D. Rothstein: Johns Hopkins University School of Medicine
Leslie M. Thompson: University of California
Dhruv Sareen: Cedars-Sinai Medical Center
Clive N. Svendsen: Cedars-Sinai Medical Center
Ernest Fraenkel: Massachusetts Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.

Date: 2024
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DOI: 10.1038/s41467-024-47758-8

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