TY - JOUR
T1 - Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
AU - Barshad, Gilad
AU - Blumberg, Amit
AU - Cohen, Tal
AU - Mishmar, Dan
N1 - Funding Information: The authors thank Dr. Alal Eran, Prof. Hermona Soreq, Dr. Esti Yeger-Lotem, Dr. Barak Rotblat, Prof. Ofer Ovadia, Prof. Avraham Zangen, and Dr. Noam Barnea-Yigael for deep and insightful discussions on the brain-specific expression pattern found in this study. The authors acknowledge the Darom Scholarship for excellent PhD students awarded to G.B. This work was supported by the United States–Israel Binational Science Foundation (2013060) and the US Army Life Sciences Division (67993LS). Funding Information: The authors thank Dr. Alal Eran, Prof. Hermona Soreq, Dr. Esti Yeger-Lotem, Dr. Barak Rotblat, Prof. Ofer Ovadia, Prof. Avraham Zangen, and Dr. Noam Barnea-Yigael for deep and insightful discussions on the brain-specific expression pattern found in this study. The authors acknowledge the Darom Scholarship for excellent PhD students awarded to G.B. This work was supported by the United States-Israel Binational Science Foundation (2013060) and the US Army Life Sciences Division (67993LS). Publisher Copyright: © 2018 Barshad et al.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049234685&partnerID=8YFLogxK
U2 - https://doi.org/10.1101/gr.226324.117
DO - https://doi.org/10.1101/gr.226324.117
M3 - Article
C2 - 29903725
SN - 1088-9051
VL - 28
SP - 952
EP - 967
JO - Genome Research
JF - Genome Research
IS - 7
ER -