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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE99335 | GEO | 2018/01/01

SECONDARY ACCESSION(S): PRJNA388150

REPOSITORIES: GEO

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Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation

Project description: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.

2017-12-23 | GSE92641 | GEO

Identificaiton of novel acetylation sites in UHRF1 mediated by acetyltransferase MOF

Project description:The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (Males absent On the First) is an acetyltransferase of UHRF1 to acetylate UHRF1 at Lys670 in the pre-RING linker region whereas HDAC1 is a deacetylase of UHRF1 at the same site. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity and elimination of UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs the DNMT1 recruitment and DNA methylation. Taken together, these findings not only identify MOF as a new acetyltransferase for UHRF1 but also reveal a novel mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.

2024-03-06 | PXD040426 | Pride

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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Uhrf1 control the proliferation and the differentiation of satellite cells

Project description: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.

2022-02-04 | GSE169193 | GEO

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric control of H3 ubiquitylation by UHRF1

Project description:DNA methylation is a heritable chromatin modification essential to mammalian development that functions with histone post-translational modifications to regulate chromatin structure and gene expression programs. The epigenetic inheritance of DNA methylation requires the combined actions of DNMT1 and UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that facilitates DNMT1 recruitment to sites of newly replicated DNA through the ubiquitylation of histone H3. UHRF1 binds DNA with modest selectivity towards hemi-methylated CpG dinucleotides (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation inheritance but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. We further show that HeDNA functions as an allosteric regulator of UHRF1 ubiquitin ligase activity, directing ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies define a highly orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.

2016-08-25 | PXD003983 | Pride

Effect of MOF mediated UHRF1 acetylation on global DNA methyaltion maintenance in mouse embryonic stem cells.

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Downregulation of Uhrf1 activity by TGF-β signaling controls Foxp3 methylation and iTreg cell differentiation

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.

2019-09-08 | GSE128480 | GEO

Ubiquitome analysis of UHRF1 and UHRF2-deficient mESCs

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

Critical role of the UBL-domain in stimulating the E3 ubiquitin ligase activity of UHRF1 towards chromatin

Project description:The RING E3 ubiquitin ligase UHRF1 controls DNA methylation through its ability to target the maintenance DNA methyltransferase DNMT1 to newly replicated chromatin. DNMT1 recruitment relies on ubiquitylation of histone H3 by UHRF1, however, how UHRF1 deposits ubiquitin onto the histone is unknown. Here, we demonstrate that the ubiquitin-like domain (UBL) of UHRF1 is essential for RINGmediated H3 ubiquitylation. Using chemical crosslinking and mass spectrometry, biochemical assays and recombinant chromatin substrates we show that the UBL participates in structural rearrangements of UHRF1 upon binding to chromatin and the E2 ubiquitin conjugating enzyme UbcH5a/UBE2D1. Similar to ubiquitin, the UBL exerts its effects through a hydrophobic patch that contacts a regulatory surface on the “backside” of the E2 to stabilise the E2-E3-chromatin complex. Our analysis of the enzymatic mechanism of UHRF1 uncovers an unexpected function of the UBLdomain and defines a new role for this domain in DNMT1-dependent inheritance of DNA methylation.

2018-11-04 | PXD011510 | Pride

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