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Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation

ABSTRACT: Chondrocyte differentiation is regulated at a transcriptional level and by various hormonal stimuli. Since chondrocyte differentiation is important for normal skeletal growth, inadequate amounts of differentiation can lead to pathological conditions such as osteoarthritis. Transcriptional regulation can be tightly orchestrated by epigenetic regulators. Among these, ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) is reported to have diverse epigenetic functions, including regulation of DNA methylation. However, the physiological functions of Uhrf1 in skeletal tissues remain unclear. Here we show that limb mesenchymal cell-specific Uhrf1 conditional knockout mice (Uhrf1ΔLimb/ΔLimb) exhibit shortened long bones that have morphological deformities due to impaired chondrocyte differentiation and proliferation. RNA-seq performed on primary cultured chondrocytes obtained from control and Uhrf1ΔLimb/ΔLimb mice revealed that expression levels of proliferative chondrocyte marker genes were downregulated, whereas hypertrophic chondrocyte marker genes were upregulated. In addition, gene ontology analyses and Gene Set Enrichment Analysis (GSEA) suggested that limb growth retardation due to compromised chondrocyte differentiation might be caused by increased activity of the focal adhesion signaling pathway. These results indicated that Uhrf1 has a crucial role in normal skeletal maturation by coordinating transcriptional regulatory networks during chondrocyte differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE92641 | GEO | 2017/12/23

SECONDARY ACCESSION(S): PRJNA358213

REPOSITORIES: GEO

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Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression

Project description:Transcriptional regulation can be tightly orchestrated by epigenetic regulators. Among these, ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) is reported to have diverse epigenetic functions, including regulation of DNA methylation. However, the physiological functions of Uhrf1 in skeletal tissues remain unclear. Here we show that limb mesenchymal cell-specific Uhrf1 conditional knockout mice (Uhrf1ΔLimb/ΔLimb) exhibit remarkably shortened long bones that have morphological deformities due to dysregulated chondrocyte differentiation as well as proliferation. RNA-seq performed on primary cultured chondrocytes obtained from Uhrf1ΔLimb/ΔLimb mice demonstrates abnormal acceleration of chondrocyte differentiation. In addition, integrative analyses using RNA-seq and MBD-seq reveal that Uhrf1 deficiency cause decreased genome-wide DNA methylation status and reduction in the promoters of specific genes such as Hspb1, which affects chondrocyte differentiation. These results indicate that Uhrf1 governs cell-type specific transcriptional regulation through genome-wide DNA methylation alteration and regulates consequent cell differentiation and skeletal maturation.

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