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Early and late RNA eQTL are driven by different genetic mechanisms.
Saori Sakaue1,2,3,4, , Soumya Raychaudhuri5,6,7,8
1Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nature Communications
|April 25, 2026
Summary
This study distinguishes genetic regulation of RNA abundance by comparing nuclear and cellular expression quantitative trait loci (eQTL). Nuclear eQTL suggest transcriptional control, while cellular eQTL indicate post-transcriptional mechanisms, revealing distinct regulatory pathways.
Area of Science:
- Genomics
- Molecular Biology
- Systems Biology
Background:
- Understanding genetic regulation of RNA abundance is crucial for disease mechanism elucidation.
- Conventional expression quantitative trait loci (eQTL) studies assess steady-state RNA, encompassing the entire transcript lifecycle.
- eQTL effects can originate from nuclear transcriptional regulation or post-transcriptional cytoplasmic events like RNA modification or stability.
Purpose of the Study:
- To differentiate between transcriptional and post-transcriptional regulatory mechanisms of gene expression.
- To compare eQTL derived from mature cellular RNA versus recently transcribed nuclear RNA.
- To investigate the distinct genetic variants and regulatory elements associated with nuclear and cellular eQTL.
Main Methods:
- Comparative analysis of eQTL from mature cellular RNA and nascent nuclear RNA in brain and kidney tissues.
- Identification of distinct causal variants for cellular and nuclear eQTL.
- Enrichment analysis of eQTL variants in transcribed regions and distal regulatory elements.
Main Results:
- Distinct causal variants were identified for cellular and nuclear eQTL affecting the same eGenes.
- Cellular eQTL were enriched in transcribed regions, supporting post-transcriptional regulation.
- Nuclear eQTL were enriched in distal regulatory elements, consistent with transcriptional control.
- Specific examples include stop-gain variants in cellular eQTL (implicating nonsense-mediated decay) and nuclear eQTL variants within enhancers (e.g., TUBGCP4) colocalizing with disease loci like schizophrenia.
Conclusions:
- Genetic regulation of RNA abundance involves distinct nuclear (transcriptional) and cytoplasmic (post-transcriptional) mechanisms.
- Analysis of nuclear RNA provides insights into transcriptional regulation, while cellular RNA reflects post-transcriptional effects.
- This distinction is vital for understanding gene expression variation and its link to complex diseases.
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