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Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene
Michiko Yamashita1,2, Kazuki Inoue3, Noritaka Saeki1,3
1Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Toon, Ehime 791-0295, Japan.
Development (Cambridge, England)
|November 29, 2017
Summary
Ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) is crucial for skeletal development. Uhrf1 deficiency in limb cells disrupts DNA methylation, leading to abnormal chondrocyte differentiation and shortened long bones.
Area of Science:
- Epigenetics
- Skeletal Biology
- Transcriptional Regulation
Background:
- Epigenetic regulators orchestrate transcriptional control.
- Ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) has known epigenetic functions, including DNA methylation regulation.
- The role of Uhrf1 in skeletal tissue physiology is not well understood.
Purpose of the Study:
- To investigate the physiological functions of Uhrf1 in skeletal tissues.
- To elucidate the role of Uhrf1 in chondrocyte differentiation and skeletal maturation.
Main Methods:
- Generation of limb mesenchymal cell-specific Uhrf1 conditional knockout mice (Uhrf1Δ).
- RNA sequencing (RNA-seq) of primary chondrocytes from Uhrf1Δ mice.
- Methylated DNA-binding domain sequencing (MBD-seq) combined with RNA-seq for integrative analysis.
Main Results:
- Uhrf1Δ mice displayed significantly shortened long bones with morphological deformities.
- Abnormal chondrocyte differentiation and proliferation were observed in Uhrf1Δ mice.
- Uhrf1 deficiency led to decreased genome-wide DNA methylation and altered gene expression, particularly at promoter regions of genes like Hspb1.
- Hspb1 knockdown partially normalized chondrocyte differentiation gene expression in Uhrf1Δ chondrocytes.
Conclusions:
- Uhrf1 is essential for regulating cell type-specific transcription in skeletal development.
- Uhrf1 controls genome-wide DNA methylation status, impacting chondrocyte differentiation and skeletal maturation.
- Dysregulation of Uhrf1-mediated DNA methylation contributes to skeletal deformities.
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