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Analysis of subcellular RNA fractions demonstrates significant genetic regulation of gene expression in human brain post-transcriptionally

D'Sa, Karishma; Guelfi, Sebastian; Vandrovcova, Jana; Reynolds, Regina H; Zhang, David; Hardy, John; Botía, Juan A; ... Ryten, Mina; + view all (2023) Analysis of subcellular RNA fractions demonstrates significant genetic regulation of gene expression in human brain post-transcriptionally. Scientific Reports , 13 (1) , Article 13874. 10.1038/s41598-023-40324-0. Green open access

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Abstract

Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.

Type: Article
Title: Analysis of subcellular RNA fractions demonstrates significant genetic regulation of gene expression in human brain post-transcriptionally
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-023-40324-0
Publisher version: https://doi.org/10.1038/s41598-023-40324-0
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Gene regulation, Molecular neuroscience, Transcriptomics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10175881
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