No abstract

Most cell functions are carried out by interacting factors, thus underlying the functional importance of genetic interactions between genes, termed epistasis. Epistasis could be under strong selective pressures especially in conditions where the mutation rate of one of the interacting partners notably differs from the other. Accordingly, the order of magnitude higher mitochondrial DNA (mtDNA) mutation rate as compared to the nuclear DNA (nDNA) of all tested animals, should influence systems involving mitochondrial-nuclear (mito-nuclear) interactions. Such is the case of the energy producing oxidative phosphorylation (OXPHOS) and mitochondrial translational machineries which are comprised of factors encoded by both the mtDNA and the nDNA. Additionally, the mitochondrial RNA transcription and mtDNA replication systems are operated by nDNA-encoded proteins that bind mtDNA regulatory elements. As these systems are central to cell life there is strong selection toward mito-nuclear co-evolution to maintain their function. However, it is unclear whether (A) mito-nuclear co-evolution befalls only to retain mitochondrial functions during evolution or, also, (B) serves as an adaptive tool to adjust for the evolving energetic demands as species’ complexity increases. As the first step to answer these questions we discuss evidence of both negative and adaptive (positive) selection acting on the mtDNA and nDNA-encoded genes and the effect of both types of selection on mito-nuclear interacting factors. Emphasis is given to the crucial role of recurrent ancient (nodal) mutations in such selective events. We apply this point-of-view to the three available types of mito-nuclear co-evolution: protein–protein (within the OXPHOS system), protein-RNA (mainly within the mitochondrial ribosome), and protein-DNA (at the mitochondrial replication and transcription machineries).

Compatibility between the nuclear (nDNA) and mitochondrial (mtDNA) genomes is important for organismal health. However, its significance for major evolutionary processes such as speciation is unclear, especially in vertebrates. We previously identified a sharp mtDNA-specific sequence divergence between morphologically indistinguishable chameleon populations (Chamaeleo chamaeleon recticrista) across an ancient Israeli marine barrier (Jezreel Valley). Because mtDNA introgression and gender-based dispersal were ruled out, we hypothesized that mtDNA spatial division was maintained by mito-nuclear functional compensation. Here, we studied RNA-seq generated from each of ten chameleons representing the north and south populations and identified candidate nonsynonymous substitutions (NSSs) matching the mtDNA spatial distribution. The most prominent NSS occurred in 14 nDNA-encoded mitochondrial proteins. Increased chameleon sample size (N = 70) confirmed the geographic differentiation in POLRMT, NDUFA5, ACO1, LYRM4, MARS2, and ACAD9. Structural and functionality evaluation of these NSSs revealed high functionality. Mathematical modeling suggested that this mito-nuclear spatial divergence is consistent with hybrid breakdown. We conclude that our presented evidence and mathematical model underline mito-nuclear interactions as a likely role player in incipient speciation in vertebrates.

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 (), which associates with high OXPHOS activity, at the expense of , 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.

How enhancers control target gene expression over long genomic distances remains an important unsolved problem. Here we studied enhancer-promoter contact architecture and communication by integrating data from nucleosome-resolution genomic contact maps, nascent transcription, and perturbations to transcription-associated proteins and thousands of candidate enhancers. Contact frequency between functionally validated enhancer-promoter pairs was most enriched near the +1 and +2 nucleosomes at enhancers and target promoters, indicating that functional enhancer-promoter pairs spend time in close physical proximity. Blocking RNA polymerase II (Pol II) caused major disruptions to enhancer-promoter contacts. Paused Pol II occupancy and the enzymatic activity of poly (ADP-ribose) polymerase 1 (PARP1) stabilized enhancer-promoter contacts. Based on our ndings, we propose an updated model that couples transcriptional dynamics and enhancer-promoter communication.