TY - JOUR
T1 - Contrasting effects of whole-body and hepatocyte-specific deletion of the RNA polymerase III repressor Maf1 in the mouse
AU - Willemin, Gilles
AU - Mange, François
AU - Praz, Viviane
AU - Lorrain, Séverine
AU - Cousin, Pascal
AU - Roger, Catherine
AU - Willis, Ian M.
AU - Hernandez, Nouria
N1 - Publisher Copyright:
Copyright © 2023 Willemin, Mange, Praz, Lorrain, Cousin, Roger, Willis and Hernandez.
PY - 2023
Y1 - 2023
N2 - 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 pre-tRNA 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.
AB - 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 pre-tRNA 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.
KW - ChIPseq
KW - RNAseq
KW - angiogenin
KW - growth hormone
KW - lipogenesis
KW - metabolic regulation
KW - proteomics
KW - transcription repressor
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U2 - 10.3389/fmolb.2023.1297800
DO - 10.3389/fmolb.2023.1297800
M3 - Article
AN - SCOPUS:85180427651
SN - 2296-889X
VL - 10
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 1297800
ER -