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

Autor: D'Sa K; Department of Neurodegenerative Disease, University College London, London, WC1N 3BG, UK.; Department of Medical & Molecular Genetics, School of Medical Sciences, King's College London, Guy's Hospital, London, SE1 1UL, UK.; Department of Clinical and Movement Neurosciences, University College London, London, WC1N 3BG, UK., Guelfi S; Department of Neurodegenerative Disease, University College London, London, WC1N 3BG, UK.; Verge Genomics, Tower Pl, South San Francisco, CA, 94080, USA., Vandrovcova J; Dept of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Reynolds RH; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, WC1N 1EH, UK., Zhang D; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, WC1N 1EH, UK., Hardy J; Department of Neurodegenerative Disease, University College London, London, WC1N 3BG, UK.; UK Dementia Research Institute at University College London, London, WC1N 3BG, UK., Botía JA; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, WC1N 1EH, UK.; Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, 30100, Murcia, Spain., Weale ME; Department of Medical & Molecular Genetics, School of Medical Sciences, King's College London, Guy's Hospital, London, SE1 1UL, UK.; Genomics Plc, Oxford, OX1 1JD, UK., Taliun SAG; Department of Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada.; Montréal Heart Institute, Montréal, QC, H1T 1C8, Canada.; Department of Neurosciences, Université de Montréal, Montréal, QC, H3T 1J4, Canada., Small KS; Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK., Ryten M; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, WC1N 1EH, UK. mina.ryten@ucl.ac.uk.; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, WC1N 3JH, UK. mina.ryten@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Aug 24; Vol. 13 (1), pp. 13874. Date of Electronic Publication: 2023 Aug 24.
DOI: 10.1038/s41598-023-40324-0
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje