The nuclear bodies formed by histone demethylase KDM7A.
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ABSTRACT:
SUBMITTER: Ming H
PROVIDER: S-EPMC8019015 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent emerging evidences revealed that epigenetic methylation of histone and DNA regulates the lineage commitment of mesenchymal progenitor cells. This study was undertaken to delineate the actions of histone lysine demethylase 7A (KDM7A) on osteogenic and adipogenic differentiation. Kdm7a expression was up-regulated in primary marrow stromal cells and established stromal ST2 line after adipogenic and osteogenic treatment. Silencing of endogenous Kdm7a in the cells blocked adipogenic differentiation whereas promoted osteogenic differentiation. Conversely, overexpression of wild-type Kdm7a in the progenitor cells enhanced adipogenic differentiation whereas inhibited osteogenic differentiation. However, the effect of KDM7A on cell differentiation was largely attenuated when the point mutation was made that abolishes enzymatic activity of KDM7A. Mechanism investigations revealed that silencing of Kdm7a down-regulated the expression of the CCAAT/enhancer binding protein ? (C/EBP?) and secreted frizzled-related protein 1 (Sfrp1). Chromatin immunoprecipitation (ChIP) assay revealed that KDM7A directly binds to the promoters of C/EBP? and Sfrp1 and removes the histone methylation marks H3K9me2 and H3K27me2. Furthermore, silencing of Kdm7a activated canonical Wnt signalling. Thereafter, activation of canonical Wnt signalling through silencing of Sfrp1 in ST2 attenuated the stimulation of adipogenic differentiation and inhibition of osteogenic differentiation by KDM7A. Our study suggests that KDM7A balances adipogenic and osteogenic differentiation from progenitor cells through epigenetic control of C/EBP? and canonical Wnt signalling and implicates that control of KDM7A action has an epigenetic perspective of curtailing metabolic disorders like osteoporosis.
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Project description:The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.
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Project description:Lysine demethylase KDM7A removes histone modifications H3K9me1/2 and H3K27me1/2. KDM7A plays critical roles in gene expression and contribute to biological processes including tumorigenesis, metabolism, and embryonic development. However, the functions of KDM7A in mammalian nervous system are still poorly explored. In this study, functional roles of KDM7A are comprehensively investigated in neuronal cells by applying CUT&Tag-seq, RNA-seq and mice models. Knockdown of Kdm7a in N2A cells result in the alteration of histone modifications near transcription start sites (TSSs) and the expression changes of a large number of genes. In particular, the expression of immediate early genes (IEGs), a series of genes maintaining the function of the nervous system and associating with neurological disorders, are significantly decreased upon Kdm7a knockdown. Furthermore, in vivo knockdown of Kdm7a in dentate gyrus (DG) neuron of mice hippocampus, via Adeno-associated virus (AAV)-based stereotaxic microinjection, led to a significant decrease of the expression of c-Fos, a marker of neuron activity. Behavior assays in mice further revealed that Kdm7a knockdown in hippocampus repress neuron activity, which leading to impairment of emotion and memory. Collectively, the study reveals that KDM7A affects neuron functions by regulating IEGs, which may provide new clues for understanding epigenetic mechanisms in neurological disorders.
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Project description:There is growing evidence that histone lysine demethylases (KDMs) play critical roles in the regulation of embryo development. This study investigated if KDM7A, a lysine demethylase known to act on mono-(me1) and di-(me2) methylation of H3K9 and H3K27, participates in the regulation of early embryo development. Knockdown of KDM7A mRNA reduced blastocyst formation by 69.2% in in vitro fertilized (IVF), 48.4% in parthenogenetically activated (PA), and 48.1% in somatic cell nuclear transfer (SCNT) embryos compared to controls. Global immunofluorescence (IF) signal in KDM7A knockdown compared to control embryos was increased for H3K27me1 on D7, for H3K27me2 on D3 and D5, for H3K9me1 on D5 and D7, and for H3K9me2 on D5 embryos, but decreased for H3K9me1, me2 and me3 on D3. Moreover, KDM7A knockdown altered mRNA expression, including the downregulation of KDM3C on D3, NANOG on D5 and D7, and OCT4 on D7 embryos, and the upregulation of CDX2, KDM4B and KDM6B on D5 embryos. On D3 and D5 embryos, total cell number and mRNA expression of embryo genome activation (EGA) markers (EIF1AX and PPP1R15B) were not affected by KDM7A knockdown. However, the ratio of inner cell mass (ICM)/total number of cells in D7 blastocysts was reduced by 45.5% in KDM7A knockdown compared to control embryos. These findings support a critical role for KDM7A in the regulation of early development and cell lineage specification in porcine embryos, which is likely mediated through the modulation of H3K9me1/me2 and H3K27me1/me2 levels, and changes in the expression of other KDMs and pluripotency genes.
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Project description:Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder cancer cells, especially under drug-resistant conditions. When the KDM7A gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.
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Project description:JMJD3 H3K27me3 demethylase plays an important role in the transcriptional response to different signaling pathways; however, the mechanism by which it facilitates transcription has been unclear. Here we show that JMJD3 regulates transcription of transforming growth factor β (TGFβ)-responsive genes by promoting RNA polymerase II (RNAPII) progression along the gene bodies. Using chromatin immunoprecipitation followed by sequencing experiments, we show that, upon TGFβ treatment, JMJD3 and elongating RNAPII colocalize extensively along the intragenic regions of TGFβ target genes. According to these data, genome-wide analysis shows that JMJD3-dependent TGFβ target genes are enriched in H3K27me3 before TGFβ signaling pathway activation. Further molecular analyses demonstrate that JMJD3 demethylates H3K27me3 along the gene bodies, paving the way for the RNAPII progression. Overall these findings uncover the mechanism by which JMJD3 facilitates transcriptional activation.
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Project description:Methylation of histone H3-lysine 9 (H3K9) and H3K27 by the methyltransferase G9a and polycomb repressive complex 2 (PRC2) inhibits transcription of target genes. A crosstalk between G9a and PRC2 via direct physical interaction has been shown recently. Here, we demonstrate an alternative mechanism by which G9a promotes H3K27 methylation. Overexpression of G9a increases both H3K9 and H3K27 methylation, reduces E-cadherin expression, and induces epithelial-mesenchymal transition in PANC-1 pancreatic cancer cells. Conversely, the depletion of G9a or ectopic expression of methyltransferase-dead G9a in G9a-overexpressing gemcitabine-resistant PANC-1-R cells exhibits opposite effects. G9a promotes H3K27 methylation of the E-cadherin promoter by upregulating PCL3 to increase PRC2 promoter recruitment and by downregulating the H3K27 demethylase KDM7A to silence E-cadherin gene. The depletion of PCL3 or overexpression of KDM7A elevated expression of E-cadherin in PANC-1-R cells while ectopic expression of PCL3 or knockdown of KDM7A downregulated E-cadherin in PANC-1 cells. Collectively, we provide evidence that G9a orchestrates the dynamic balance within histone-modifying enzymes to regulate H3K27 methylation and gene expression.
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Project description:Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate that deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the p53 pathway resulting in a block to terminal differentiation.
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