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Çelik, M.H.* ; Gagneur, J. ; Lim, R.G.* ; Wu, J.* ; Thompson, L.M.* ; Xie, X.*

Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers.

HGG Advances 5:100318 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The high heritability of 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 ChIP-seq 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Aberrant Gene Expression ; Amyotrophic Lateral Sclerosis (als) ; Chromatin Accessibility ; Epigenetics ; Motor Neuron Disease ; Multiomics ; Outlier Detection ; Post-transcriptional Regulation ; Rare Disease ; Transcriptional Regulation; Model; Bcl-2; Distinct; Genome; Gene
ISSN (print) / ISBN 2666-2477
e-ISSN 2666-2477
Journal Human Genetics and Genomics Advances
Quellenangaben Volume: 5, Issue: 3, Pages: , Article Number: 100318 Supplement: ,
Publisher Cell Press
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants UCI IPH Pilot Award
National Science Foundation
Robert Packard Center for ALS Research at Johns Hopkins