Single-Cell Multiomics of the Human Retina Reveals Hierarchical Transcription Factor Collaboration in Mediating Cell Type-Specific Effects of Genetic Variants on Gene Regulation

Authors

Jun Wang
Xuesen Cheng
Qingnan Liang
Leah A Owen
Jiaxiong Lu
Yiqiao Zheng
Meng Wang
Shiming Chen
Margaret M DeAngelis
Yumei Li
Rui Chen

Publication Date

11-27-2023

Journal

Genome Biology

DOI

10.1186/s13059-023-03111-8

PMID

38012720

PMCID

PMC10680294

PubMedCentral® Posted Date

11-27-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Transcription Factors, Multiomics, Quantitative Trait Loci, Gene Expression Regulation, Chromatin, Genome-Wide Association Study, Genetic variants, Gene regulation, Transcription factor collaboration, Cell type-specific effect, eQTL, caQTL, ASE, ASCA, Single-cell multiomics, The human retina

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.

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