Maf1 and Repression of RNA Polymerase III-Mediated Transcription Drive Adipocyte Differentiation

Chen, Chun-Yuan; Lanz, Rainer B.; Walkey, Christopher J.; Chang, Wei-Feng; Lu, Wange; Johnson, Deborah L.

doi:10.1016/j.celrep.2018.07.046

Cited by 28 publications

(43 citation statements)

References 46 publications

(73 reference statements)

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“…Pol II transcriptome profiling of liver from fed Maf1 -/and WT mice identified a set of ~1000 differentially expressed genes. A similar number of differentially expressed genes were reported in undifferentiated NIH3T3-L1 cells following MAF1 knockdown 16 . However, the two profiles contained few overlapping genes and were not similar by a rank-rank hypergeometric test.…”

Section: Discussionsupporting

confidence: 74%

“…More recently, RNA-seq data has been reported following Maf1 knockdown in mouse NIH3T3-L1 cells, a fibroblast-like cell line that can be chemically-induced to differentiate into adipocytes 16 .…”

Section: Analysis Of the Pol II Transcriptome In Maf1 -/Livermentioning

confidence: 99%

“…In C. elegans, increasing or decreasing MAF1 levels causes reciprocal changes in body area. Strikingly, in worms and in cultured mammalian cells, perturbation of MAF1 levels correlates with changes in >1000 mRNAs 15,16 . Common effects of MAF1 on the expression of fatty acid synthase (Fasn) and acetyl CoA carboxylase alpha (Acaca) have been found in worms and mammalian cells and is correlated with changes in fat accumulation 15,17 .…”

Section: Introductionmentioning

confidence: 99%

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MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse

Bonhoure

Praz

Moir

et al. 2019

Preprint

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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 fed and fasted mice, however the impact of the feeding-fasting cycle on pol III function has not been examined. Here we show that changes in pol III occupancy in the liver of fed versus fasted 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 fed and fasted 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. Affiliations

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Section: Discussionsupporting

confidence: 74%

Section: Analysis Of the Pol II Transcriptome In Maf1 -/Livermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse

Bonhoure

Praz

Moir

et al. 2019

Preprint

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“…The ability of Maf1 to affect body composition and metabolism under this model is supported by its function in mammals as chronic Pol III repressor whose activity can be enhanced by limiting nutrients and stressors 13,14 . Maf1 expression also promotes the differentiation of mouse embryonic stem cells into mesoderm and the differentiation of NIH3T3-L1 cells into adipocytes 15 . These studies demonstrate the central role of Pol III transcription and its inhibition by Maf1 in diverse aspects of organismal physiology.…”

Section: Introductionmentioning

confidence: 98%

Structural basis of RNA polymerase III transcription repression by Maf1

Vorländer¹,

Baudin²,

Moir³

et al. 2019

Preprint

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Maf1 is a highly conserved central regulator of transcription by RNA polymerase III (Pol III), and Maf1 activity influences a wide range of phenotypes from metabolic efficiency to lifespan. Here, we present a 3.3 Å cryo-EM structure of yeast Maf1 bound to Pol III, which establishes how Maf1 achieves transcription repression. In the Maf1-bound state, Pol III elements that are involved in transcription initiation are sequestered, and the active site is sealed off due to ordering of the mobile C34 winged helix 2 domain. Specifically, the Maf1 binding site overlaps with the binding site of the Pol III transcription factor TFIIIB and DNA in the pre-initiation complex, rationalizing that binding of Maf1 and TFIIIB to Pol III are mutually exclusive. We validate our structure using variants of Maf1 with impaired transcription-inhibition activity. These results reveal the exact mechanism of Pol III inhibition by Maf1, and rationalize previous biochemical data.

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“…S2) prompted us to investigate the roles of MAFR-1 in the germline, specifically of males. Recent work has found MAF1 expression in embryonic stem cells drives differentiation (Chen et al, 2018). C. elegans possess only one population of stem cells-the germlinewhich originate from a single cell and become progressively more mature as they migrate through the gonad away from the distal tip cell (Kimble, 1981).…”

Section: Discussionmentioning

confidence: 99%

Roles for the RNA polymerase III regulator MAFR-1 in regulating sperm quality inCaenorhabditis elegans

Hammerquist

Curran

2020

Preprint

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The negative regulator of RNA polymerase (pol) III mafr-1 has been shown to affect RNA pol III transcript abundance, lipid biosynthesis and storage, progeny output, and lifespan. We deleted mafr-1 from the Caenorhabditis elegans genome and found that animals lacking mafr-1 replicated many phenotypes from previous RNAi-based studies, but strikingly not the oocyte-related reproductive phenotypes. Utilizing a yeast two-hybrid assay, we discovered several novel interactors of MAFR-1 that are expressed in a sperm-and germline-enriched manner. In support of a role for MAFR-1 in the male germline, we found mafr-1 null males have smaller spermatids that are less capable in competition for fertilization; a phenotype that was dependent on RNA pol III activity. Restoration of MAFR-1 expression specifically in the germline rescued the spermatid-related phenotypes, suggesting a cell autonomous role for MAFR-1 in nematode male fertility. Based on the high degree of conservation of Maf1 activity across species, our study may inform similar roles for Maf1 and RNA pol III in mammalian male fertility.

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Maf1 and Repression of RNA Polymerase III-Mediated Transcription Drive Adipocyte Differentiation

Cited by 28 publications

References 46 publications

MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse

MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse

Structural basis of RNA polymerase III transcription repression by Maf1

Roles for the RNA polymerase III regulator MAFR-1 in regulating sperm quality inCaenorhabditis elegans

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