MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass.
MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass.
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MAF1是RNA聚合酶III依赖性转录的阻遏物，调节骨量。
DOI：
10.7554/elife.74740
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发表时间：
2022-05-25
期刊：
影响因子：
7.7
通讯作者：
Johnson, Deborah L.
中科院分区：
文献类型：
--
作者：
Phillips, Ellen;Ahmad, Naseer;Sun, Li;Iben, James;Walkey, Christopher J.;Rusin, Aleksandra;Yuen, Tony;Rosen, Clifford J.;Willis, Ian M.;Zaidi, Mone;Johnson, Deborah L.
MAF 1是RNA聚合酶（pol）III介导的转录的关键阻遏物，已显示在体外促进中胚层形成。在这里，我们表明MAF 1在调节成骨细胞分化和骨量中起着关键作用。MAF 1的整体缺失（Maf 1-/-小鼠）产生高骨量表型。然而，从Maf 1-/-小鼠分离的成骨细胞显示体外成骨细胞生成减少。因此，我们确定了在来自间充质谱系的细胞中过表达MAF 1的小鼠的表型（Prx 1-Cre; LSL-MAF 1小鼠）。这些小鼠表现出骨量增加。离体，来自这些小鼠的细胞显示与其高骨量表型一致的成骨细胞生成增强。因此，Maf 1-/-小鼠的高骨量表型可能是由于MAF 1整体缺失的混杂效应。MAF 1过表达促进ST 2细胞的成骨分化，而MAF 1下调抑制分化，表明MAF 1促进成骨细胞的形成。然而，其他干扰用于抑制RNA聚合酶III转录，抑制成骨细胞分化。然而，通过这些扰动降低RNA聚合酶III转录增强ST 2细胞中的脂肪形成。RNA-seq分析了这些对成骨细胞分化的相反作用的基础。用于干扰RNA pol III转录的不同模式导致不同的基因表达变化，表明该转录过程是高度敏感的，并触发不同的基因表达程序和表型结果。具体而言，MAF 1诱导已知促进成骨细胞分化的基因。此外，在成骨细胞分化过程中诱导的基因显示密码子偏好。总之，这些结果揭示了MAF 1和RNA pol III介导的转录在成骨细胞命运决定、分化和骨量调节中的新作用。
MAF1, a key repressor of RNA polymerase (pol) III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show that MAF1 plays a critical role in regulating osteoblast differentiation and bone mass. Global deletion of MAF1 (Maf1-/- mice) produced a high bone mass phenotype. However, osteoblasts isolated from Maf1-/- mice showed reduced osteoblastogenesis ex vivo. Therefore, we determined the phenotype of mice overexpressing MAF1 in cells from the mesenchymal lineage (Prx1-Cre;LSL-MAF1 mice). These mice showed increased bone mass. Ex vivo, cells from these mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1-/- mice is likely due to confounding effects from the global absence of MAF1. MAF1 overexpression promoted osteoblast differentiation of ST2 cells while MAF1 downregulation inhibited differentiation, indicating MAF1 enhances osteoblast formation. However, other perturbations used to repress RNA pol III transcription, inhibited osteoblast differentiation. However, decreasing RNA pol III transcription through these perturbations enhanced adipogenesis in ST2 cells. RNA-seq analyzed the basis for these opposing actions on osteoblast differentiation. The different 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 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, differentiation, and bone mass regulation.