Abstract
Maf1−/− mice are lean, obesity-resistant and metabolically inefficient. Their increased energy expenditure is thought to be driven by a futile RNA cycle that reprograms metabolism to meet an increased demand for nucleotides stemming from the deregulation of RNA polymerase (pol) III transcription. Metabolic changes consistent with this model have been reported in both fasted and refed mice, however the impact of the fasting-refeeding-cycle on pol III function has not been examined. Here we show that changes in pol III occupancy in the liver of fasted versus refed wild-type mice are largely confined to low and intermediate occupancy genes; high occupancy genes are unchanged. However, in Maf1−/− mice, pol III occupancy of the vast majority of active loci in liver and the levels of specific precursor tRNAs in this tissue and other organs are higher than wild-type in both fasted and refed conditions. Thus, MAF1 functions as a chronic repressor of active pol III loci and can modulate transcription under different conditions. Our findings support the futile RNA cycle hypothesis, elaborate the mechanism of pol III repression by MAF1 and demonstrate a modest effect of MAF1 on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins.
Highlights
The synthesis of the translational apparatus is energetically costly and, subject to tight regulation (see[1] and references therein)
A key feature of this hypothesis is the existence of a homeostatic mechanism for pol III transcripts, most notably mature tRNAs, that keeps their cellular levels largely constant when pol III transcription is increased by deletion of Maf[1]
The preceding observations and parallel findings in serum starved human fibroblasts[9] indicate that active pol III loci can be partitioned into two groups based on pol III occupancy; one that is sensitive to nutrient signals and one that is not very sensitive to these signals
Summary
The synthesis of the translational apparatus is energetically costly and, subject to tight regulation (see[1] and references therein). Studies with fasted mice revealed elevated pol III transcription and precursor tRNA levels in the liver and numerous others tissues (~ 3 to 9 fold changes in precursor tRNAs) but no change in total tRNA or mature tRNA levels These and other findings led to the proposal of a futile RNA cycle to account for the lean phenotype and wasteful use of metabolic energy in Maf1−/− mice 11. In Maf1−/− mice, pol III occupancy was increased for the majority of active loci in liver, regardless of their occupancy level, and the levels of specific precursor tRNAs in this tissue and in other organs are higher than wild-type in both fasted and refed conditions. We report changes in the pol II transcriptome in refed liver and a modest reduction in global translation in the refed state that reflects decreased mRNA levels and/or translation efficiencies of certain ribosomal proteins
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