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

作者：Stanislav Tsitkov, Kelsey Valentine, Velina Kozareva, Aneesh Donde, Aaron P. Frank, Susan Lei, Michael J. Workman, Ryan G. Lim, Jie Wu, Zhuoxing Wu, Loren Ornelas, Lindsay Panther, Erick Galvez, Daniel I. Pérez, Imara Meepe, Viviana Valencia, Emilda Gomez, Chunyan Liu, Ruby Moran, Louis Pinedo, Ritchie Ho, Julia Kaye, Terri G. Thompson, Dillon Shear, Robert W. Baloh, Maria G. Bañuelos, Veronica J. Garcia, Ronald Holewenski, О Э Карпов, Danica-Mae Manalo, Berhan Mandefro, Andrea Matlock, Rakhi Pandey, Niveda Sundararaman, Hannah Trost, Vineet Vaibhav, Vidya Venkatraman, Oliver Wang, Jonathan D. Glass, Arish Jamil, Naufa Amirani, Leandro de Araújo Lima, Krishna Raja, Wesley Robinson, Reuben Thomas, Edward Vertudes, Stacia K. Wyman, Carla Agurto, Guillermo Cecchi, Raquel Norel, Omar Ahmad, Emily G. Baxi, Aianna Cerezo, Alyssa N. Coyne, Lindsey R. Hayes, John W. Krakauer, Nicholas J. Maragakis, Elizabeth Mosmiller, Promit Roy, Steven R. Zeiler, Miriam Adam, Noura Albistami, Tobias Ehrenberger, Nhan Huynh, Connie New, Alex Lenail, Jonathan Li, Natasha Leanna Patel-Murray, Yogindra Raghav, Divya Ramamoorthy, Egun Im, Karen Sachs, Brook T. Wassie, James D. Berry, Merit Cudkowicz, Alanna Farrar, Sara Thrower, Sarah Luppino, Lindsay Pothier, Alexander Sherman, Ervin Sinani, Prasha Vigneswaran, Hong Yu, Jay C. Beavers, Mary Bellard, Elizabeth Bruce, Senda Ajroud‐Driss, Deniz Alibazoglu, Ben Joslin, Matthew B. Harms, Sarah Heintzman, Stephen J. Kolb, Carolyn Prina, Daragh Heitzman, Todd E. Morgan, Ricardo Miramontes, Jennifer Stocksdale, Keona Q. Wang, Jennifer Jockel‐Balsarotti, Elizabeth Karanja, Jesse Markway, Molly McCallum, T. W. Miller, Jennifer Roggenbuck, Jennifer E. Van Eyk, Steven Finkbeiner, Jeffrey D. Rothstein, Leslie M. Thompson, Dhruv Sareen, Clive N. Svendsen, Ernest Fraenkel · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-47758-8 · 被引用次数：13 · 研究领域：Amyotrophic Lateral Sclerosis Research、Epigenetics and DNA Methylation、Neurogenetic and Muscular Disorders Research

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.