Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
- Wayne State University, United States
- University of Chicago, United States
- UCLA, United States
- University of Michigan, United States
- Henry Ford Hospital, United States
Abstract
Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.
Data availability
Sequencing files have been uploaded to the Sequence Read Archive (SRA) under Bioproject PRJNA694697
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Gene expression of LCLs, IPSCs, and CMs following 28 perturbationsNCBI Bioproject, PRJNA694697.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM109215)
- Roger Pique-Regi
- Francesca Luca
National Institute of General Medical Sciences (R35GM131726)
- Yoav Gilad
National Institute of General Medical Sciences (F30GM131580)
- Anthony S Findley
National Institute of General Medical Sciences (R35GM125055)
- Sriram Sankararaman
National Science Foundation (III-1705121)
- Ali Pazokitoroudi
- Sriram Sankararaman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Stephen CJ Parker, University of Michigan, United States
Version history
- Received: February 1, 2021
- Accepted: May 13, 2021
- Accepted Manuscript published: May 14, 2021 (version 1)
- Version of Record published: July 1, 2021 (version 2)
Copyright
© 2021, Findley et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
eLife 10:e67077.
https://doi.org/10.7554/eLife.67077
Further reading
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- Cell Biology
- Chromosomes and Gene Expression
Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.
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- Chromosomes and Gene Expression
Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription-site-proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.
