Chromosome conformation capture of all 13 genomic Loci in the transcriptional regulation of the multisubunit bigenomic cytochrome C oxidase in neurons.

Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain composed of 13 subunits; three are mitochondria-encoded, and 10 are nucleus-inscribed on nine different chromosomes within the mammalian genome. The transcriptional regulation of such a multisubunit, multichromosomal, and bigenomic enzyme is mechanistically challenging. Transcription factories have been proposed as one mechanism by which genes from different genomic loci congregate to transcribe functionally related genes, and chromosome conformation capture (3C) is a means by which such interactions can be revealed. Thus far, however, only loci from the same chromosome or at most two chromosomes have been co-localized by 3C. The present study used 3C to test our hypothesis that not only the 10 genomic loci from nine chromosomes encoding the 10 nuclear subunits of COX, but also genes from three chromosomes encoding mitochondrial transcription factors A and B (Tfam, Tfb1m, and Tfb2m) critical for the transcription of the three mitochondria-encoded COX subunit genes all occupy common intranuclear sites in the murine neuronal nuclei. The pairing of various COX subunit genes and Tf genes indicates that interactions are present among all of them. On the other hand, genes for a non-mitochondrial protein (calreticulin) as well as a mitochondrial enzyme (citrate synthase) did not interact with COX genes. Furthermore, interactions between COX subunit and Tf genes were up-regulated by depolarizing stimulation and down-regulated by impulse blockade in primary neurons. Thus, a viable mechanism is in place for a synchronized, coordinated transcriptional regulation of this multisubunit, bigenomic COX enzyme in neurons.