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

Genome Res. 2018 Jul;28(7):952-967. doi: 10.1101/gr.226324.117. Epub 2018 Jun 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Brain / metabolism*
  • Cell Nucleus / genetics*
  • DNA, Mitochondrial / genetics*
  • Glycolysis / genetics
  • Humans
  • Isoenzymes / genetics
  • L-Lactate Dehydrogenase / genetics
  • Mitochondria / genetics*
  • Neurons / metabolism
  • Oxidative Phosphorylation
  • Protein Isoforms / genetics

Substances

  • DNA, Mitochondrial
  • Isoenzymes
  • Protein Isoforms
  • L-Lactate Dehydrogenase
  • lactate dehydrogenase 1