Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers
Muhammed Hasan Çelik,
Julien Gagneur,
Ryan G. Lim,
Jie Wu,
Leslie M. Thompson,
Xiaohui Xie
Affiliations
Muhammed Hasan Çelik
Department of Computer Science, University of California Irvine, Irvine, CA, USA; Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA
Julien Gagneur
Department of Informatics, Technical University of Munich, Garching, Germany; Helmholtz Association - Munich School for Data Science (MUDS), Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
Ryan G. Lim
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA
Jie Wu
Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
Leslie M. Thompson
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA; UCI MIND, University of California Irvine, Irvine, CA, USA; Department of Psychiatry and Human Behavior and Sue and Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA, USA; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA
Xiaohui Xie
Department of Computer Science, University of California Irvine, Irvine, CA, USA; Corresponding author
Summary: The high heritability of amyotrophic lateral sclerosis (ALS) contrasts with its low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. To aid the exploration of these factors, we introduced EpiOut, an algorithm to identify chromatin accessibility outliers that are regions exhibiting divergent accessibility from the population baseline in a single or few samples. Annotation of accessible regions with histone chromatin immunoprecipitation sequencing and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is available at github.com/uci-cbcl/EpiOut.
