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The IRE1?-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix.

ABSTRACT: During skeletal development, osteoblasts produce large amounts of extracellular matrix proteins and must therefore increase their secretory machinery to handle the deposition. The accumulation of unfolded protein in the endoplasmic reticulum induces an adoptive mechanism called the unfolded protein response (UPR). We show that one of the most crucial UPR mediators, inositol-requiring protein 1? (IRE1?), and its target transcription factor X-box binding protein 1 (XBP1), are essential for bone morphogenic protein 2-induced osteoblast differentiation. Furthermore, we identify Osterix (Osx, a transcription factor that is indispensible for bone formation) as a target gene of XBP1. The promoter region of the Osx gene encodes two potential binding motifs for XBP1, and we show that XBP1 binds to these regions. Thus, the IRE1?-XBP1 pathway is involved in osteoblast differentiation through promoting Osx transcription.

SUBMITTER: Tohmonda T

PROVIDER: S-EPMC3090012 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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The IRE1α-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix.

Tohmonda Takahide T Miyauchi Yoshiteru Y Ghosh Rajarshi R Yoda Masaki M Uchikawa Shinichi S Takito Jiro J Morioka Hideo H Nakamura Masaya M Iwawaki Takao T Chiba Kazuhiro K Toyama Yoshiaki Y Urano Fumihiko F Horiuchi Keisuke K

EMBO reports 20110318 5

During skeletal development, osteoblasts produce large amounts of extracellular matrix proteins and must therefore increase their secretory machinery to handle the deposition. The accumulation of unfolded protein in the endoplasmic reticulum induces an adoptive mechanism called the unfolded protein response (UPR). We show that one of the most crucial UPR mediators, inositol-requiring protein 1α (IRE1α), and its target transcription factor X-box binding protein 1 (XBP1), are essential for bone mo ...[more]

PMID: 21415858

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Project description:Commitment of Runx2-expressing precursor osteoblasts to functional osteoblasts and then to osteocytes is triggered by Osterix (Osx), which activates its target genes in those cells during bone formation. It is not yet known whether Osx has a role in remodeling the chromatin architecture of its target genes during the transition from preosteoblast to osteoblast. In testing the hypothesis that Osx is indispensable for active chromatin architecture, we first showed that in Osx-null calvarial cells occupancy of the transcriptional activators, including lysine 4 methyl transferase (Wdr5), c-Myc, and H2A.Z, at the Osx target gene Bsp was very markedly decreased. The levels of methylation of lysines 4 and 36 and acetylation of histone H3, markers for active chromatin, were also reduced at the Bsp gene in these cells. In contrast, occupancy of the transcriptional repressors HP1 and the nucleolar protein 66 (NO66), a histone demethylase previously identified as an Osx-interacting protein, was increased at the Bsp gene in Osx-null calvarial cells. Furthermore, the Bsp promoter was hypermethylated in embryonic stem (ES) cells and in embryonic day 9.5 (E9.5) embryos but was markedly hypomethylated in the calvaria of E18.5 embryos, coinciding with robust Bsp expression. In contrast, CpG methylation in the Bsp promoter remained high in Osx-null calvaria compared to Osx-wild-type calvaria. Our data also revealed that NO66 interacted with DNA Methyltransferase 1A (DNMT1A), histone deacetylase 1A (HDAC1A), and HP1, which are known to control histone and DNA methylation. In addition, HP1 stimulated the demethylase activity of NO66 for its substrates "trimethylation of histone H3 at lysine 4" (H3K4me3) and "trimethylation of histone H3 at lysine 36" (H3K36me3). Our findings strongly suggest that in the absence of Osx, the chromatin of Osx target genes is transcriptionally inactive. We propose that Osx is a molecular switch for the formation of an active chromatin state during osteoblast differentiation, whereas NO66 helps gene repression through histone demethylation and/or formation of a repressor complex, resulting in multilayered control of the chromatin architecture of specific osteoblast genes.

Dataset Information

The IRE1?-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix.

Publications

The IRE1α-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix.

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