Histone H3K27 demethylase, Utx, regulates osteoblast-to-osteocyte differentiation

Osteocytes are master regulators of skeletal homeostasis. However, little is known about the molecular mechanism of their differentiation. Epigenetic regulations, especially H3K27me3 modification, play critical roles in cell differentiation. Here, we found that H3K27me3 in the loci of osteocyte-expr...

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Published in:Biochemical and biophysical research communications 2022-01, Vol.590, p.132-138
Main Authors: Xia, Yuhan, Ikedo, Aoi, Lee, Ji-Won, Iimura, Tadahiro, Inoue, Kazuki, Imai, Yuuki
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Bone
Bone Diseases, Metabolic - genetics
Cancellous Bone - diagnostic imaging
Cancellous Bone - pathology
Cell Count
Cell Differentiation - genetics
Down-Regulation - genetics
Epigenetics
Epigenome
Genetic Loci
H3K27me3
Histone Demethylases - deficiency
Histone Demethylases - metabolism
Histones - metabolism
Lysine - metabolism
Methylation
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteoblasts - cytology
Osteoblasts - metabolism
Osteocytes
Osteocytes - cytology
Osteocytes - metabolism
Phenotype
Protein Processing, Post-Translational
Transcriptome - genetics
Utx
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Summary:Osteocytes are master regulators of skeletal homeostasis. However, little is known about the molecular mechanism of their differentiation. Epigenetic regulations, especially H3K27me3 modification, play critical roles in cell differentiation. Here, we found that H3K27me3 in the loci of osteocyte-expressing genes decreased during osteocyte differentiation and that H3K27me3 demethylase, Utx, was bound to the loci of those genes. To investigate the physiological functions of Utx in vivo, we generated late osteoblast-to-osteocyte specific Utx knockout mice using Dmp1-cre mice (UtxΔOcy/ΔOcy). Micro CT analyses showed that UtxΔOcy/ΔOcy displayed osteopenic phenotypes with lower bone volume and trabecular number, and greater trabecular separation. Bone histomorphometric analysis showed that bone mineralization and formation were significantly lower in UtxΔOcy/ΔOcy. Furthermore, Dmp1 expression and the number of osteocytes were significantly decreased in UtxΔOcy/ΔOcy. These results suggest that Utx in Dmp1-expressing osteoblast/osteocyte positively regulates osteoblast-to-osteocyte differentiation through H3K27me3 modifications in osteocyte genes. Our results provide new insight into the molecular mechanism of osteocyte differentiation. •H3K27me3 is negatively correlated with the expression of upregulated genes during osteocyte differentiation.•Utx binds to the regulatory regions of critical osteocyte genes such as Sost, Dmp1, Mepe and Dkk1.•UtxΔOcy/ΔOcy exhibits osteopenic phenotype with reduced bone formation.•UtxΔOcy/ΔOcy displays reduced Dmp1 expression and the number of osteocytes.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2021.12.102