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Contrasting effects of whole-body and hepatocyte-specific deletion of the RNA polymerase III repressor Maf1 in the mouse [RNA-Seq]

ABSTRACT: MAF1 is a nutrient-sensitive, TORC1-regulated repressor of RNA polymerase III (Pol III). MAF1 downregulation leads to increased lipogenesis in Drosophila melanogaster, Caenorhabditis elegans, and mice. However, Maf1−/− mice are lean as increased lipogenesis is counterbalanced by futile pre-tRNA synthesis and degradation, resulting in increased energy expenditure. We compared Chow-fed Maf1−/− mice with Chow- or High Fat (HF)-fed Maf1hep−/− mice that lack MAF1 specifically in hepatocytes. Unlike Maf1−/− mice, Maf1hep−/− mice become heavier and fattier than control mice with old age and much earlier under a HF diet. Liver ChIPseq, RNAseq and proteomics analyses indicate increased Pol III occupancy at Pol III genes, very few differences in mRNA accumulation, and protein accumulation changes consistent with increased lipogenesis. Futile pretRNA synthesis and degradation in the liver, as likely occurs in Maf1hep−/− mice, thus seems insufficient to counteract increased lipogenesis. Indeed, RNAseq and metabolite profiling indicate that liver phenotypes of Maf1−/− mice are strongly influenced by systemic inter-organ communication. Among common changes in the three phenotypically distinct cohorts, Angiogenin downregulation is likely linked to increased Pol III occupancy of tRNA genes in the Angiogenin promoter.

ORGANISM(S): Mus musculus

PROVIDER: GSE224743 | GEO | 2023/11/28

REPOSITORIES: GEO

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Contrasting effects of whole-body and hepatocyte-specific deletion of the RNA polymerase III repressor Maf1 in the mouse [ChIP-Seq]

Project description:MAF1 is a nutrient-sensitive, TORC1-regulated repressor of RNA polymerase III (Pol III). MAF1 downregulation leads to increased lipogenesis in Drosophila melanogaster, Caenorhabditis elegans, and mice. However, Maf1−/− mice are lean as increased lipogenesis is counterbalanced by futile pre-tRNA synthesis and degradation, resulting in increased energy expenditure. We compared Chow-fed Maf1−/− mice with Chow- or High Fat (HF)-fed Maf1hep−/− mice that lack MAF1 specifically in hepatocytes. Unlike Maf1−/− mice, Maf1hep−/− mice become heavier and fattier than control mice with old age and much earlier under a HF diet. Liver ChIPseq, RNAseq and proteomics analyses indicate increased Pol III occupancy at Pol III genes, very few differences in mRNA accumulation, and protein accumulation changes consistent with increased lipogenesis. Futile pretRNA synthesis and degradation in the liver, as likely occurs in Maf1hep−/− mice, thus seems insufficient to counteract increased lipogenesis. Indeed, RNAseq and metabolite profiling indicate that liver phenotypes of Maf1−/− mice are strongly influenced by systemic inter-organ communication. Among common changes in the three phenotypically distinct cohorts, Angiogenin downregulation is likely linked to increased Pol III occupancy of tRNA genes in the Angiogenin promoter.

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Contrasting effects of whole-body and hepatocyte-specific deletion of the RNA polymerase III repressor Maf1 in the mouse

Project description:The conserved phosphoprotein MAF1 is the main known direct repressor of RNA polymerase III (Pol III). MAF1 is phosphorylated and inactivated by the nutrient-sensing TORC1 kinase, making MAF1 a nutrient effector for Pol III transcription. MAF1 has been associated with lipid metabolism in D. melanogaster, C. elegans, and the mouse. However, whereas downregulation of Maf1 generally increases lipogenesis, Maf1-/- mice are lean even under a High Fat (HF) diet. Here we compared Maf1-/- mice fed a Chow diet with mice lacking Maf1 specifically in hepatocytes (Maf1hep-/- mice) fed either a Chow or HF diet. Unlike Maf1-/- mice, Maf1hep-/- mice become slightly heavier than control mice at an old age and much earlier under a HF diet, with increased adiposity. Liver ChIPseq, RNAseq and proteomics analyses indicate increased Pol III occupancy at Pol III genes, very few differences in mRNA accumulation, and subtle changes in protein accumulation that are consistent with increased lipogenesis. RNAseq and metabolite profiling indicate that liver phenotypes of Maf1-/- mice are strongly influenced by systemic inter-organ communication. Notable changes observed in the three phenotypically distinct cohorts include downregulation of Mouse Urinary Proteins, upregulation of Cyp2a4 expression, suggestive of an alteration of Growth Hormone levels or secretion pattern, and downregulation of Angiogenin, a phenomenon that might be directly linked to increased Pol III occupancy of tRNA genes in the main Angiogenin promoter region.

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Project description:RNA polymerase III (pol III) synthesizes short non-coding RNAs, many of which, including tRNAs, Rpph1 RNA, Rn5s rRNA, and Rmrp RNA, are essential for translation. Accordingly, pol III activity is tightly regulated with cell growth and proliferation by factors such as MYC, RB1, TRP53, and MAF1. MAF1 is a repressor of pol III transcription whose activity is controlled by phosphorylation; in particular, it is inactivated through phosphorylation by mTORC1 kinase, a sensor of nutrient availability. Pol III regulation is thus sensitive to environmental cues, yet a diurnal profile of pol III transcription activity is so far lacking. Here we document pol III occupancy of its target genes in mouse liver during the diurnal cycle and show that pol III occupancy rises before the onset of the night, stays high during the night, when mice normally ingest food and when translation is increased, and decreases in daytime. By comparing diurnal pol III occupancy in wild-type mice, arrhythmic mice owing to inactivation of the Arntl gene, mice fed at regular intervals during both night and day, and mice lacking the Maf1 gene, we show that whereas higher pol III occupancy during the night reflects a MAF1-dependent response to feeding, the rise of pol III occupancy before the onset of the night reflects a circadian clock-dependent response. Thus, pol III transcription during the diurnal cycle is regulated both in response to nutrients and by the circadian clock, which allows anticipatory pol III transcription.

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