Title | Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Wang, J, Cheng, X, Liang, Q, Owen, LA, Lu, J, Zheng, Y, Wang, M, Chen, S, DeAngelis, MM, Li, Y, Chen, R |
Journal | Genome Biol |
Volume | 24 |
Issue | 1 |
Pagination | 269 |
Date Published | 2023 Nov 27 |
ISSN | 1474-760X |
Keywords | Chromatin, Gene Expression Regulation, Genome-Wide Association Study, Humans, Multiomics, Quantitative Trait Loci, Transcription Factors |
Abstract | BACKGROUND: Systematic characterization of how genetic variation modulates gene regulation in a cell type-specific context is essential for understanding complex traits. To address this question, we profile gene expression and chromatin accessibility in cells from healthy retinae of 20 human donors through single-cell multiomics and genomic sequencing. RESULTS: We map eQTL, caQTL, allelic-specific expression, and allelic-specific chromatin accessibility in major retinal cell types. By integrating these results, we identify and characterize regulatory elements and genetic variants effective on gene regulation in individual cell types. The majority of identified sc-eQTLs and sc-caQTLs display cell type-specific effects, while the cis-elements containing genetic variants with cell type-specific effects are often accessible in multiple cell types. Furthermore, the transcription factors whose binding sites are perturbed by genetic variants tend to have higher expression levels in the cell types where the variants exert their effects, compared to the cell types where the variants have no impact. We further validate our findings with high-throughput reporter assays. Lastly, we identify the enriched cell types, candidate causal variants and genes, and cell type-specific regulatory mechanism underlying GWAS loci. CONCLUSIONS: Overall, genetic effects on gene regulation are highly context dependent. Our results suggest that cell type-dependent genetic effect is driven by precise modulation of both trans-factor expression and chromatin accessibility of cis-elements. Our findings indicate hierarchical collaboration among transcription factors plays a crucial role in mediating cell type-specific effects of genetic variants on gene regulation. |
DOI | 10.1186/s13059-023-03111-8 |
Alternate Journal | Genome Biol |
PubMed ID | 38012720 |
PubMed Central ID | PMC10680294 |
Grant List | R01EY020540 / EY / NEI NIH HHS / United States S10OD023469 / NH / NIH HHS / United States R01EY018571 / EY / NEI NIH HHS / United States R01 EY018571 / EY / NEI NIH HHS / United States R01 EY027784 / EY / NEI NIH HHS / United States R01 EY032136 / EY / NEI NIH HHS / United States P30 EY002687 / EY / NEI NIH HHS / United States P30 EY002687 / NH / NIH HHS / United States S10OD025240 / NH / NIH HHS / United States R01EY022356 / EY / NEI NIH HHS / United States P30 EY002520 / NH / NIH HHS / United States R01 EY012543 / EY / NEI NIH HHS / United States BR-GE-0613-0618-BCM / FFB / Foundation Fighting Blindness / United States R01 EY022356 / EY / NEI NIH HHS / United States R01 EY020540 / EY / NEI NIH HHS / United States S10 OD023469 / OD / NIH HHS / United States S10 OD025240 / OD / NIH HHS / United States R21 CA200504 / CA / NCI NIH HHS / United States |
Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation.
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