Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming

Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.

Research progress of JMJD3 in Parkinson's disease / 中国药理学通报

Parkinson's disease is a common neurodegenerative disease in middle-aged and elderly people, in which the pathogenic factors are not yet clear. Genetics, dietary habits, environmental toxins, immunological abnormalities, inflammation and oxidative stress response, apoptosis, and mitochondrial dysfunctions which caused by a variety of physiological and biogenic changes are likely to exacerbate the occurrence of Parkinson's disease. In recent years, studies have shown that the activity of microglia is closely related to Parkinson's disease, and that the active microglia can promote the release of inflammatory factors, while the differentiation of dopamine neurons in the substantial nigra of midbrain area is also closely related to Parkinson's disease. As a histone H3K27me3 demethylase, JMJD3 is involved and affects the activity of microglia, which can regulate the polarization of microglia as well and affect the survival of dopaminergic neurons in the mesencephalon. This provides new methods and strategies for treating Parkinson' s disease. This paper summarizes the structure and function of JMJD3, as well as its role in neuro-inflammation mediated by microglia and its effect on neurons, and explores the functions and related research progress of JMJD3 in Parkinson's disease.

Effects of JMJD3 on DOX-induced cardiotoxicity through regulating STAT3 / 中国药理学通报

Aim To investigate the regulatory relationship and mechanism of JMJD3 and STAT3 in DOX-induced cardiotoxicity. Methods To establish the model of cardiotoxicity in vitro and in vivo, H9C2cells were treated with DOX(1 μmol · L-1) for 12 hours; Sprague-Dawley rats were subcutaneously injected with a cumulative dose of 15 mg · kg-1DOX. The adenovirus encoding JMJD3 (Ad-JMJD3) was transduced into the rat left ventricle via intramyocardial injection. The recombinant adenovirus (Ad-JMJD3 or Ad-STAT3) infection were used to overexpress JMJD3 or STAT3 in cardiomyocytes. Knockdown JMJD3 was achieved by transfecting with siRNA of JMJD3 in H9C2cells. The method of TMRE was used to detect the mitochondrial membrane depolarization. Results The model of cardiotoxicity was successfully built both in vivo and in vitro by DOX. The mRNA and protein level of JMJD3 in DOX-induced cardiotoxicity both in vivo and in vitro were significantly raised compared with those of control or NC group. Ad-JMJD3 significantly aggravated the damage effect of H9C2cells induced by DOX. JMJD3 knockdown could significantly relieve DOX-induced apoptosis. Ad-STAT3 could obviously attenuate DOX-or Ad-JMJD3-induced apoptosis-related protein expression. Both DOX and Ad-JMJD3 could inhibit the protein expression and phosphorylation level of STAT3. Conclusions DOX caused the up-regulation of protein expression of JMJD3, inhibited STAT3 and p-STAT3 protein expression, thus, aggravating cardiotoxicity.

Association of JMJD3, MMP-2 and VEGF expressions with clinicopathological features of invasive ductal breast carcinoma / 南方医科大学学报

OBJECTIVE@#To examine the expressions of JMJD3, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in invasive ductal breast carcinoma, their association with the clinicopathological features of the patients and the effect of JMJD3 overexpression on proliferation and MMP-2 and VEGF expressions in breast cancer cells.@*METHODS@#The protein and mRNA expressions of JMJD3, MMP-2, and VEGF in invasive ductal breast carcinoma and paired adjacent tissues were detected by immunohistochemistry and RT-PCR, respectively, and their correlation with the clinicopathological characteristics of the patients was analyzed. Kaplan-Meier survival analysis was used to evaluate the correlation of JMJD3, MMP-2 and VEGF expression levels with the survival of the patients. In breast cancer MDA-MB-231 cells transfected with a JMJD3-expression plasmid, the expression of Ki67 was examined immunohistochemically, the cell proliferation was assessed with CCK8 assay, and the mRNA expressions of MMP-2 and VEGF were detected with RT-PCR.@*RESULTS@#Breast cancer tissues had significantly lower JMJD3 expression and higher MMP-2 and VEGF expressions at both the mRNA and protein levels than the adjacent tissue (@*CONCLUSIONS@#The expressions of JMJD3, MMP-2 and VEGF in invasive ductal breast carcinoma are closely correlated to tumor proliferation, invasion, metastasis and prognosis and can be used for prognostic evaluation of breast cancer.

HistonedemethylaseJMJD3promotesthestemnessofdiffuselargeBcelllymphoma cells / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the effect of histone demethylase JMJD3 (jumonji domain-containing protein 3) on the stemness of diffuse large B-cell lymphoma (DLBCL) cells. Methods: The relationship between the expression of JMJD3 and the overall survival of DLBCL patients was analyzed using the clinical data of DLBCL patients in TCGA database. The control plasmid (pCMV) and JMJD3 expression plasmid(pCMV-JMJD3)weretransfectedintoDLBCLcellsofABCandGCBsubtype via lipofectamine transfection. Then, the mRNAlevels of JMJD3,ALDH1, OCT4 and SOX2 were detected by RT-PCR and qPCR; the activity ofALDH1 enzyme was detected by Flow cytometry; the protein expressions of OCT4 and SOX2 were detected by Western blotting. Gene enrichment in DLBCL patients with high JMJD3 expression was analyzed by gene set enrichment analysis (GSEA). Results: The result of prognosis analysis showed that high expression of JMJD3 was related with poor prognosis in DLBCL patients (P<0.05); however, multivariate analysis showed that the expression of JMJD3 was not the independent factor affecting the prognosis of DLBCL patients (all P>0.05). The expression of JMJD3 was remarkably increased in DLBCL cells transfected with pCMV-JMJD3, which led to significantly increased mRNA level and enzyme activity of ALDH1 as well as up-regulated mRNA and protein expressions of OCT4 and SOX2 (P<0.05 or P<0.01). GSEA analysis showed that enrichment of Wnt/β-catenin signaling pathway related gene set was observed in DLBCL patients with high JMJD3 expression (P<0.05). Conclusion: JMJD3 promotes the stemness of DLBCL cells, which may be a potential therapeutic target for DLBCL patients.

Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter

Polycomb chromobox (CBX) proteins regulate gene transcription by maintaining chromatin states, which guide a variety of biological processes. Now, epigenetic regulation of innate immune response is an emerging field. However, the role of CBX proteins in innate immunity remains unclear. We confirmed that the expression of CBX family proteins, especially Cbx2, was decreased in macrophages upon viral infection, and then we investigated the role of Cbx2 in the antiviral immune response. Silencing or knockdown of Cbx2 in macrophages inhibited virus-induced production of IFN-β. Furthermore, heterozygous Cbx2 knockout were susceptible to VSV challenge. Mechanistically, Cbx2 binds to and recruits Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased transcription of IFN-β. Together, our study reveals a non-traditional function of a Cbx protein and adds new insight into the epigenetic regulation of antiviral innate immunity.

Influence of RNAi inhibiting JMJD3 gene expression on growth,proliferation and invasion of hepatocellular carcinoma cells / 国际检验医学杂志

Objective To study the influence of small interfering RNA(siRNA) inhibiting Jumonji-containing JMJD3 gene on growth,proliferation and invasion of hepatocellular carcinoma cells.Methods JMJD3 was silenced by RNA interference(siR-JMJD3),non-specificity sequence pSilercer 2.1 was transfected into liver cancer cells QGY 7703 and HepG2 cells as the negative control.MTT assay,colony formation and Transwell invasion assays were used to detect the cell growth,proliferation and invasion ability of hepatocellular carcinoma cells.Results The Western Blot detection results showed that the siR-JMJD3 plasmid transfected experiment group successfully inhibited the JMJD3 protein expression level in liver cancer cells.The MTT results showed that after transfecting siR-JMJD3,the growth activity of QGY-7703 and HepG2 were decreased by 25% or 17% compared with the control group,.The colony formation results showed that in the colony formation number of two cell lines were decreased by 31% and 25% respectively.The Transwell invasion test results indicated that transmembrane cells number was decreased by 44% and 47% respectively.Conclusion Using siRNA technique can effectively inhibit JMJD3 gene expression,meanwhile effectively inhibits the in vitro growth,proliferation and invasion of liver cancer cells QGY-7703 and HepG2 and provides a new thinking for the biological therapy of liver cancer.

The Expression of JMJD3 and its role for cell proliferation and apoptosis in Human gastric Carcinoma / 实用医学杂志

Objective To investigate the expression of JMJD3 and its functions for cell growth in human gastric carcinoma.Methods The expression of JMJD3 was detected by immunohistochemistry.Recombinant JMJD3 plasmids were transfected into MGC-803 cells.Cell proliferation was determined by CCK-8 assay and cell apoptosis was detected by flow cytometry.Results The expression of JMJD3 was down-regulated in gastric carcinoma tissues (P ＜ 0.05).Low expression of JMJD3 was associated with advanced TNM stage (Ⅲ+Ⅳ,P ＜ 0.05).Overexpression of JMJD3 could inhibit cell proliferation and induce cell apoptosis (P ＜ 0.05).Conclusion Low expression of JMJD3 was commonly existed in gastric cancer.JMJD3 could inhibit cell proliferation and induce cell apoptosis.

H3 K27 me3 demethylase Jmjd3 regulates proliferation and differentiation of embryonal lung epithelia of mice / 基础医学与临床

Objective To investigate the role of H3K27me3 demethylase Jmjd3(KDM6B) during the development of lung in embryonal mice .Methods Jmjd3 knockout embryos of E 19.5 mice were examined by HE , PAS and immnohistochemistry assays .Results The developmental defects of the lung of Jmjd 3 heterozygous ( Jmjd3 +/-) embryos were mild is compared to Jmjd3 +/+embryos.However, Jmjd3 -/-mice suffered from the severe hypoplasia of lung tissue .Differentiated defects of ciliated cell , Clara cell , type Ⅰ and Ⅱ alveolar epithelial cells were ob-served in Jmjd3 -/-embryos.The index of cell proliferation was increased in Jmjd3 -/-embryos as compared to wildtype and Jmjd3 +/- embryos.No difference in apoptosis profile was found in these embryos .Conclusions Jmjd3 is essential for proliferation and differentiation of embryonal lung epithelia of mice .