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Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation

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...

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Autores principales: Wang, Jun, Cheng, Xuesen, Liang, Qingnan, Owen, Leah A., Lu, Jiaxiong, Zheng, Yiqiao, Wang, Meng, Chen, Shiming, DeAngelis, Margaret M., Li, Yumei, Chen, Rui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680294/
https://www.ncbi.nlm.nih.gov/pubmed/38012720
http://dx.doi.org/10.1186/s13059-023-03111-8
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author Wang, Jun
Cheng, Xuesen
Liang, Qingnan
Owen, Leah A.
Lu, Jiaxiong
Zheng, Yiqiao
Wang, Meng
Chen, Shiming
DeAngelis, Margaret M.
Li, Yumei
Chen, Rui
author_facet Wang, Jun
Cheng, Xuesen
Liang, Qingnan
Owen, Leah A.
Lu, Jiaxiong
Zheng, Yiqiao
Wang, Meng
Chen, Shiming
DeAngelis, Margaret M.
Li, Yumei
Chen, Rui
author_sort Wang, Jun
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-03111-8.
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spelling pubmed-106802942023-11-27 Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation Wang, Jun Cheng, Xuesen Liang, Qingnan Owen, Leah A. Lu, Jiaxiong Zheng, Yiqiao Wang, Meng Chen, Shiming DeAngelis, Margaret M. Li, Yumei Chen, Rui Genome Biol Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-03111-8. BioMed Central 2023-11-27 /pmc/articles/PMC10680294/ /pubmed/38012720 http://dx.doi.org/10.1186/s13059-023-03111-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Jun
Cheng, Xuesen
Liang, Qingnan
Owen, Leah A.
Lu, Jiaxiong
Zheng, Yiqiao
Wang, Meng
Chen, Shiming
DeAngelis, Margaret M.
Li, Yumei
Chen, Rui
Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation
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
title_full Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation
title_fullStr Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation
title_full_unstemmed Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation
title_short Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation
title_sort single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680294/
https://www.ncbi.nlm.nih.gov/pubmed/38012720
http://dx.doi.org/10.1186/s13059-023-03111-8
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