GSE99335
Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression
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 (Uhrf1?Limb/?Limb) 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 Uhrf1?Limb/?Limb 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. Overall design: DNA methylation profiles of primary chondrocytes obtained from Control and cKO mice were analyzed using MBD2 mediated methylated DNA enrichment followed by next generation sequencing (MBD-seq) with Illumina MiSeq.