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Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes

Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA)- and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic coregulation is poorly understood. To address this...

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Autores principales: Barshad, Gilad, Blumberg, Amit, Cohen, Tal, Mishmar, Dan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028125/
https://www.ncbi.nlm.nih.gov/pubmed/29903725
http://dx.doi.org/10.1101/gr.226324.117
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author Barshad, Gilad
Blumberg, Amit
Cohen, Tal
Mishmar, Dan
author_facet Barshad, Gilad
Blumberg, Amit
Cohen, Tal
Mishmar, Dan
author_sort Barshad, Gilad
collection PubMed
description Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA)- and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic coregulation is poorly understood. To address this question, we analyzed ∼8500 RNA-seq experiments from 48 human body sites. Despite well-known variation in mitochondrial activity, quantity, and morphology, we found overall positive mtDNA-nDNA OXPHOS genes’ co-expression across human tissues. Nevertheless, negative mtDNA-nDNA gene expression correlation was identified in the hypothalamus, basal ganglia, and amygdala (subcortical brain regions, collectively termed the “primitive” brain). Single-cell RNA-seq analysis of mouse and human brains revealed that this phenomenon is evolutionarily conserved, and both are influenced by brain cell types (involving excitatory/inhibitory neurons and nonneuronal cells) and by their spatial brain location. As the “primitive” brain is highly oxidative, we hypothesized that such negative mtDNA-nDNA co-expression likely controls for the high mtDNA transcript levels, which enforce tight OXPHOS regulation, rather than rewiring toward glycolysis. Accordingly, we found “primitive” brain-specific up-regulation of lactate dehydrogenase B (LDHB), which associates with high OXPHOS activity, at the expense of LDHA, which promotes glycolysis. Analyses of co-expression, DNase-seq, and ChIP-seq experiments revealed candidate RNA-binding proteins and CEBPB as the best regulatory candidates to explain these phenomena. Finally, cross-tissue expression analysis unearthed tissue-dependent splice variants and OXPHOS subunit paralogs and allowed revising the list of canonical OXPHOS transcripts. Taken together, our analysis provides a comprehensive view of mito-nuclear gene co-expression across human tissues and provides overall insights into the bi-genomic regulation of mitochondrial activities.
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spelling pubmed-60281252019-01-01 Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes Barshad, Gilad Blumberg, Amit Cohen, Tal Mishmar, Dan Genome Res Research Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA)- and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic coregulation is poorly understood. To address this question, we analyzed ∼8500 RNA-seq experiments from 48 human body sites. Despite well-known variation in mitochondrial activity, quantity, and morphology, we found overall positive mtDNA-nDNA OXPHOS genes’ co-expression across human tissues. Nevertheless, negative mtDNA-nDNA gene expression correlation was identified in the hypothalamus, basal ganglia, and amygdala (subcortical brain regions, collectively termed the “primitive” brain). Single-cell RNA-seq analysis of mouse and human brains revealed that this phenomenon is evolutionarily conserved, and both are influenced by brain cell types (involving excitatory/inhibitory neurons and nonneuronal cells) and by their spatial brain location. As the “primitive” brain is highly oxidative, we hypothesized that such negative mtDNA-nDNA co-expression likely controls for the high mtDNA transcript levels, which enforce tight OXPHOS regulation, rather than rewiring toward glycolysis. Accordingly, we found “primitive” brain-specific up-regulation of lactate dehydrogenase B (LDHB), which associates with high OXPHOS activity, at the expense of LDHA, which promotes glycolysis. Analyses of co-expression, DNase-seq, and ChIP-seq experiments revealed candidate RNA-binding proteins and CEBPB as the best regulatory candidates to explain these phenomena. Finally, cross-tissue expression analysis unearthed tissue-dependent splice variants and OXPHOS subunit paralogs and allowed revising the list of canonical OXPHOS transcripts. Taken together, our analysis provides a comprehensive view of mito-nuclear gene co-expression across human tissues and provides overall insights into the bi-genomic regulation of mitochondrial activities. Cold Spring Harbor Laboratory Press 2018-07 /pmc/articles/PMC6028125/ /pubmed/29903725 http://dx.doi.org/10.1101/gr.226324.117 Text en © 2018 Barshad et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research
Barshad, Gilad
Blumberg, Amit
Cohen, Tal
Mishmar, Dan
Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
title Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
title_full Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
title_fullStr Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
title_full_unstemmed Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
title_short Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
title_sort human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028125/
https://www.ncbi.nlm.nih.gov/pubmed/29903725
http://dx.doi.org/10.1101/gr.226324.117
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