Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes.
Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes.
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DOI：
10.1101/gr.226324.117
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发表时间：
2018-07
期刊：
影响因子：
7
通讯作者：
Mishmar D
中科院分区：
文献类型：
--
作者：
Barshad G;Blumberg A;Cohen T;Mishmar D
氧化磷酸化 (OXPHOS) 是所有人体组织的基本能量来源，需要线粒体 (mtDNA) 和核 (nDNA) 编码的蛋白质亚基之间的相互作用。尽管这种相互作用是 OXPHOS 的基础，但双基因组共调控却知之甚少。为了解决这个问题，我们分析了来自 48 个人体部位的约 8500 个 RNA 测序实验。尽管众所周知线粒体活性、数量和形态存在差异，但我们发现 mtDNA-nDNA OXPHOS 基因在人体组织中总体呈阳性共表达。然而，在下丘脑、基底神经节和杏仁核（皮层下大脑区域，统称为“原始”大脑）中发现了负的 mtDNA-nDNA 基因表达相关性。对小鼠和人类大脑的单细胞 RNA-seq 分析表明，这种现象在进化上是保守的，并且两者都受到脑细胞类型（涉及兴奋性/抑制性神经元和非神经元细胞）及其大脑空间位置的影响。由于“原始”大脑是高度氧化的，我们假设这种负 mtDNA-nDNA 共表达可能控制着高 mtDNA 转录水平，从而强制执行严格的 OXPHOS 调节，而不是重新连接到糖酵解。因此，我们发现乳酸脱氢酶 B (LDHB) 的“原始”大脑特异性上调与高 OXPHOS 活性相关，但会损害促进糖酵解的 LDHA。对共表达、DNase-seq 和 ChIP-seq 实验的分析表明，候选 RNA 结合蛋白和 CEBPB 是解释这些现象的最佳候选调控蛋白。最后，跨组织表达分析发现了组织依赖性剪接变体和 OXPHOS 亚基旁系同源物，并允许修改规范的 OXPHOS 转录物列表。总而言之，我们的分析提供了跨人体组织的线粒体核基因共表达的全面视图，并提供了对线粒体活动的双基因组调控的全面见解。
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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