Mitochondrial Nuclear Gene Research Articles

Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders

Transcription factors and histone modifications are crucial regulators of gene expression that mutually influence each other. We present the DNA binding profiles of upstream stimulatory factors 1 and 2 (USF1, USF2) and acetylated histone H3 (H3ac) in a liver cell line for the whole human genome using ChIP-chip at a resolution of 35 base pairs. We determined that these three proteins bind mostly in proximity of protein coding genes transcription start sites (TSSs), and their bindings are positively correlated with gene expression levels. Based on the spatial and functional relationship between USFs and H3ac at protein coding gene promoters, we found similar promoter architecture for known genes and the novel and less-characterized transcripts human mRNAs and spliced ESTs. Furthermore, our analysis revealed a previously underestimated abundance of genes in a bidirectional conformation, where USFs are bound in between TSSs. After taking into account this promoter conformation, the results indicate that H3ac is mainly located downstream of TSS, and it is at this genomic location where it positively correlates with gene expression. Finally, USF1, which is associated to familial combined hyperlipidemia, was found to bind and potentially regulate nuclear mitochondrial genes as well as genes for lipid and cholesterol metabolism, frequently in collaboration with GA binding protein transcription factor alpha (GABPA, nuclear respiratory factor 2 [NRF-2]). This expands our understanding about the transcriptional control of metabolic processes and its alteration in metabolic disorders.

Genome‐scale predictions and profiles of mitochondrial function

Mitochondria are tiny organelles found in nearly all cells, serving as the center stage for ATP production, ion homeostasis, and apoptosis. Their molecular composition, structure, and efficiency are dynamic, varying across cell types and adapting to environmental cues. Mitochondrial dysfunction can contribute to numerous, rare metabolic disorders as well as to a variety of common human diseases, such as diabetes and cancer. With the goal of systematically exploring mitochondrial function in health and in disease, we are using experimental and computational genomics to (1) assemble a high quality protein parts list for this organelle and to (2) monitor their collective behavior. We currently estimate that nearly 1500 nuclear genes encode protein components of human mitochondria. At present, only one-half are known. To predict the remaining genes, we are generating and integrating genome-scale datasets using machine learning techniques. Our methods achieve high sensitivity and specificity and identify hundreds of novel mitochondrial genes, including novel candidate disease genes. We are exploring their collective behavior by monitoring their expression with oligonucleotide microarrays. One of our key findings is that the expression of nuclear mitochondrial genes is coordinately reduced in the muscle of individuals with type 2 diabetes mellitus. We’ve developed new computational strategies that combine expression analysis with comparative sequence analysis to dissect cis-regulatory networks. Using these techniques, we’ve identified two key transcription factors that form a regulatory circuit that controls mitochondrial biogenesis in skeletal muscle. Importantly, the results identify a valuable new drug for type 2 diabetes.

Mitochondria-Nuclear Interaction in Male Sterility and Heterosis for Productivity Enhancement in Crop Plants

ABSTRACT Recent advances in genomics and transgenics have yielded some newer insights in terms of intergenomic (mitochondria-chloroplast-nuclear) communication and related molecular regulatory mechanism for the genes to function in crop plants. Mitochondrial genome mutation encodes cytoplasmic male sterility (CMS), which in turn leads to pollen abortion. CMS is the resultant of an incompatibility between the nuclear and mitochondrial genomes such that male pollen is made dysfunctional. CMS system in agriculturally important crops has been used to produce high-yielding and heterotic hybrids. Hybrid varieties generally hold immense potential for enhancing crop economic yields and productivity. An important feature of the mutation responsible for CMS is the discovery of the chimeric nature of genes and different open reading frames joined together or placed in proximal locations for cotranscriptions with other standard mitochondrial genes in the relevant genome. Genetical and molecular observations with respect to mitochondrial-nuclear genomic communications-vis-à-vis the manifestation of male sterility and heterosis–has been presented with novel interpretation. The action of mitochondrial gene(s)–when controlling the expression of nuclear gene(s) whose products have to be functionally transferred and localized within the mitochondria organelle–has been referred to as ‘retrograde regulation.’ Specific gene(s) of either mitochondrial or nuclear genomes–presumably endowed with some kind of retrograde gene regulatory mechanism–has been considered as a means by which the cell compensates for its genic inability to carry out respiratory function (electron transport-oxidative phosphorylation). The nuclear gene Rf or Fr (restorer of fertility) prevents the expression of male sterility in the CMS system in rice (B-atp 6) and maize (mitochondrial aldehyde dehydrogenase) by influencing RNA processing and sequential post-transcriptional editing. The latest findings on the subject as presented here support the notion that ‘intergenomic interaction,’ i.e., specific nuclear-mitochondrial gene's cotranscription is operational as the plausible molecular mechanism for the manifestation of male sterility and heterosis for productivity enhancement in crop plants.