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Uhrf1 control the proliferation and the differentiation of satellite cells

ABSTRACT: DNA methylation is an essential form of epigenetic regulation responsible for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are tightly regulated during differentiation. However, it is unclear how these DNA methylation patterns affect the function of satellite cells. We demonstrate that a key epigenetic regulator, ubiquitin like with PHD and RING finger domains 1 (Uhrf1), is activated in proliferating myogenic cells but not expressed in quiescent satellite cells or differentiated myogenic cells in mice. Ablation of Uhrf1 in mouse satellite cells impairs their proliferation and differentiation, leading to failed muscle regeneration. Uhrf1-deficient myogenic cells exhibited aberrant up-regulation of transcripts, including Sox9, with the reduction of DNA methylation level of their promoter and enhancer region. These findings show that Uhrf1 is a critical epigenetic regulator of proliferation and differentiation in satellite cells, by controlling cell type-specific gene expression via maintenance of DNA methylation.

ORGANISM(S): Mus musculus

PROVIDER: GSE169193 | GEO | 2022/02/04

REPOSITORIES: GEO

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Uhrf1 control the proliferation and the differentiation of satellite cells [RNA-Seq]

Project description:DNA methylation is an essential epigenetic regulation for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are dynamically changed during muscle regeneration. However, how these DNA methylation patterns are maintained remain unclear. Here, we demonstrate that a key epigenetic regulator Uhrf1 (ubiquitin-like with PHD and RING finger domains 1) is activated in proliferating but not expressed in quiescent or differentiated satellite cells. Ablation of Uhrf1 in satellite cell impairs the proliferation and differentiation of satellite cells, leading to failure of muscle regeneration. Loss of Uhrf1 in satellite cells alters transcriptional programs and leads to DNA hypomethylation with the activation of Cdkn1a and Notch signalling. Down-regulation of Cdkn1a and Notch signalling rescued the proliferation and differentiation defect in Uhrf1-deficient satellite cells. Therefore, this study suggest that Uhrf1 can regulate the self-renewal and differentiation of satellite cells through DNA methylation patterning.

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Uhrf1 control the proliferation and the differentiation of satellite cells [MBD-seq]

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Project description:The E3 ligase UHRF1 is an essential epigenetic cofactor for DNMT1 dependent maintenance DNA methylation, which provides a binding platform for DNMT1 by both cooperative binding of histones and hemi-methylated DNA as well as by ubiquitinating histone H3. Here, we conduct a comprehensive screen to identify novel ubiquitination targets of UHRF1 and its paralogue UHRF2 by comparing the ubiquitome of wildtype (wt), UHRF1- and UHRF2-deficient mouse embryonic stem cells. With an antibody-dependent enrichment of ubiquitin remnant motif-containing peptides followed by isobaric-labeling based quantitative mass spectrometry, we find both known and novel E3 ligase substrates of UHRF1 involved in a variety of biological processes such as RNA processing, DNA methylation and DNA damage repair.

2017-10-24 | PXD006593 | Pride

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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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Project description:Foxp3+ regulatory T cells (Treg cells) are essential for immune system homeostasis and suppression of excessive immune responses. Both TGF-β signaling and epigenetic modifications are important in the regulation of Foxp3 induction, but whether TGF-β signaling participates in the epigenetic regulation of Foxp3 has not been fully clarified. Here, we show that Uhrf1, which is induced by TCR stimulation and regulated by TGF-β signaling, controls Foxp3 methylation and iTreg cell differentiation. T cell-specific ablation of Uhrf1 led to Treg-biased differentiation in naïve T cells, with DNA hypomethylation upon TCR stimulation, and these Foxp3+ T cells had suppressive function. Uhrf1 maintained Foxp3 DNA methylation by recruiting Dnmt1 during cell division upon TCR stimulation. TGF-β treatment led to passive demethylation of the Foxp3 promoter to initiate its expression. Mechanistically, Uhrf1 was phosphorylated upon TGF-β stimulation and largely sequestered in the cytoplasm. Phosphorylated Uhrf1 underwent proteasomal degradation through inhibition of Usp7-mediated deubiquitination. Collectively, our study reveals a novel epigenetic mechanism of TGF-β-mediated iTreg cell differentiation regulated by Uhrf1 and reveals the differential role of active and passive demethylation in Foxp3 induction and stability.

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Gene expression profiles of uhrf1 mutant zebrafish

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Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a [RNA-Seq]

Project description:Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific cell lineage, changes in histone modifications and DNA methylation accompany the transition to more specialized cell types. Investigating how epigenetic regulation maintains pluripotency is a critical component in order to generate the required cell types for future clinical application. Uhrf1 is a widely known hemi-methylated DNA binding protein, playing a role in heterochromatin formation alongside G9a, Trim28 and HDACs. In addition, it has been demonstrated that Uhrf1 functions to maintain DNA methylation through the recruitment of Dnmt1. Although Uhrf1 is not essential in ESC self-renewal, it still remains elusive how Uhrf1 regulates pluripotency. Here, we set out to elucidate the role of Uhrf1 in pluripotent stem cells. We found that Uhrf1 forms a complex with the active trithorax group of transcriptional regulators, in particular the Setd1a/COMPASS complex. Our data show that loss of Uhrf1 causes a dramatic reduction of bivalent histone marks, in particular those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards the balance between pluripotency and differentiation via the Setd1a/COMPASSS complex, through which Uhrf1 mediates bivalent histone modifications.

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