TY - JOUR
T1 - MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass
AU - Phillips, Ellen
AU - Ahmad, Naseer
AU - Sun, Li
AU - Iben, James
AU - Walkey, Christopher J.
AU - Rusin, Aleksandra
AU - Yuen, Tony
AU - Rosen, Clifford J.
AU - Willis, Ian M.
AU - Zaidi, Mone
AU - Johnson, Deborah L.
N1 - Funding Information:
We would like to than the Genetically Engineered Rodent Models Core at the Baylor College of Medicine for assistance with mouse model production. Resources accessed through the core were supported by a National Institutes of Health grant (P30CA125123) to the Dan L. Duncan Comprehensive Cancer Center. We would like to thank Brian Dawson at Baylor College of Medicine for his help with the µCT measurements. This work was supported by NIH grants R01 CA108614 and R01 CA74138 (to D.L.J), R01 GM120358 (to I.M.W.), NIH--U19 AG060917 (M.Z.), R01 AG071870, U01 AG073148 and R01AG074092 (to M.Z. and T.Y.). M.Z. also thanks the Harrington Discovery Institute for the Innovator– Scholar Award.
Publisher Copyright:
© 2022, eLife Sciences Publications Ltd. All rights reserved.
PY - 2022/5
Y1 - 2022/5
N2 - MAF1, a key repressor of RNA polymerase III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show that MAF1 plays a critical role in the regulation of osteoblast differentiation and bone mass. A high bone mass phenotype was noted in mice with a global deletion of Maf1 (Maf1-/- mice). However, osteoblasts isolated from Maf1-/- mice showed reduced osteoblastogenesis ex vivo. Therefore, we determined the effect of MAF1 overexpression specifically in cells from the mesenchymal lineage (Prx1-Cre;LSL-MAF1 mice). These mice showed increased bone mass. Ex vivo, cells from Prx1-Cre;LSL-MAF1 mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1-/- mice is likely due to the confounding effects of the global absence of Maf1 in Maf1-/- mice. MAF1 overexpression promoted osteoblast differentiation and shRNA-mediated Maf1 downregulation inhibited differentiation of ST2 cells, overall indicating MAF1 enhances osteoblast formation. We also found that, in contrast to MAF1 overexpression, other perturbations that repress RNA pol III transcription, including Brf1 knockdown and chemical inhibition of RNA pol III by ML-60218, inhibited osteoblast differentiation. All perturbations that decrease RNA pol III transcription, however, enhanced adipogenesis in ST2 cell cultures. RNA-seq was used to determine the basis for these opposing actions on osteoblast differentiation. The modalities used to perturb RNA pol III transcription resulted in distinct gene expression changes, indicating that this transcription process is highly sensitive and triggers diverse gene expression programs and phenotypic outcomes. Specifically, MAF1 induced genes in ST2 cells known to promote osteoblast differentiation. Furthermore, genes that are induced during osteoblast differentiation displayed codon bias. Together, these results reveal a novel role for MAF1 and RNA pol III-mediated transcription in osteoblast fate determination and differentiation and bone mass regulation.
AB - MAF1, a key repressor of RNA polymerase III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show that MAF1 plays a critical role in the regulation of osteoblast differentiation and bone mass. A high bone mass phenotype was noted in mice with a global deletion of Maf1 (Maf1-/- mice). However, osteoblasts isolated from Maf1-/- mice showed reduced osteoblastogenesis ex vivo. Therefore, we determined the effect of MAF1 overexpression specifically in cells from the mesenchymal lineage (Prx1-Cre;LSL-MAF1 mice). These mice showed increased bone mass. Ex vivo, cells from Prx1-Cre;LSL-MAF1 mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1-/- mice is likely due to the confounding effects of the global absence of Maf1 in Maf1-/- mice. MAF1 overexpression promoted osteoblast differentiation and shRNA-mediated Maf1 downregulation inhibited differentiation of ST2 cells, overall indicating MAF1 enhances osteoblast formation. We also found that, in contrast to MAF1 overexpression, other perturbations that repress RNA pol III transcription, including Brf1 knockdown and chemical inhibition of RNA pol III by ML-60218, inhibited osteoblast differentiation. All perturbations that decrease RNA pol III transcription, however, enhanced adipogenesis in ST2 cell cultures. RNA-seq was used to determine the basis for these opposing actions on osteoblast differentiation. The modalities used to perturb RNA pol III transcription resulted in distinct gene expression changes, indicating that this transcription process is highly sensitive and triggers diverse gene expression programs and phenotypic outcomes. Specifically, MAF1 induced genes in ST2 cells known to promote osteoblast differentiation. Furthermore, genes that are induced during osteoblast differentiation displayed codon bias. Together, these results reveal a novel role for MAF1 and RNA pol III-mediated transcription in osteoblast fate determination and differentiation and bone mass regulation.
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U2 - 10.7554/eLife.74740
DO - 10.7554/eLife.74740
M3 - Article
C2 - 35611941
AN - SCOPUS:85131241013
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e74740
ER -