Authors: | Mitra, S.; Malik, R.; Wong, W.; Rahman, A.; Hartemink, A. J.; Pritykin, Y.; Dey, K. K.; Leslie, C. S. |
Article Title: | Single-cell multi-ome regression models identify functional and disease-associated enhancers and enable chromatin potential analysis |
Abstract: | We present a gene-level regulatory model, single-cell ATAC + RNA linking (SCARlink), which predicts single-cell gene expression and links enhancers to target genes using multi-ome (scRNA-seq and scATAC–seq co-assay) sequencing data. The approach uses regularized Poisson regression on tile-level accessibility data to jointly model all regulatory effects at a gene locus, avoiding the limitations of pairwise gene–peak correlations and dependence on peak calling. SCARlink outperformed existing gene scoring methods for imputing gene expression from chromatin accessibility across high-coverage multi-ome datasets while giving comparable to improved performance on low-coverage datasets. Shapley value analysis on trained models identified cell-type-specific gene enhancers that are validated by promoter capture Hi-C and are 11× to 15× and 5× to 12× enriched in fine-mapped eQTLs and fine-mapped genome-wide association study (GWAS) variants, respectively. We further show that SCARlink-predicted and observed gene expression vectors provide a robust way to compute a chromatin potential vector field to enable developmental trajectory analysis. © The Author(s) 2024. |
Keywords: | human cell; promoter region; genetics; nonhuman; pancreas; cd8 antigen; mouse; gene expression; erythroblast; genetic variability; gene frequency; genome-wide association study; b lymphocyte; cell specificity; skin; rna; gene expression regulation; gene mapping; cd16 antigen; chromatin; promoter regions, genetic; gene regulatory network; cd4 antigen; monocyte; t lymphocyte subpopulation; functional status; diseases; cd14 antigen; peripheral blood mononuclear cell; heritability; correlational study; transcription initiation site; enhancer region; regulatory sequences, nucleic acid; single cell analysis; single-cell analysis; regulatory sequence; hypophysis; procedures; hla dqb1 antigen; predictive model; human; article; bone marrow derived mononuclear cell; poisson regression; expression quantitative trait locus; zinc finger e box binding homeobox 2; single cell rna seq; multiomics; plasmablast; regression model; single cell atac rna linking model |
Journal Title: | Nature Genetics |
Volume: | 56 |
Issue: | 4 |
ISSN: | 1061-4036 |
Publisher: | Nature Publishing Group |
Date Published: | 2024-04-01 |
Start Page: | 627 |
End Page: | 636 |
Language: | English |
DOI: | 10.1038/s41588-024-01689-8 |
PUBMED: | 38514783 |
PROVIDER: | scopus |
PMCID: | PMC11018525 |
DOI/URL: | |
Notes: | Erratum issued, see DOI: 10.1038/s41588-024-01805-8 -- The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Christina S. Leslie -- Source: Scopus |