Role Of JARID2 Research Articles

453-P: Role of JARID2 in Regulating Inflammatory Genes via Epigenetic Mechanisms in Monocyte/Macrophages in Type 2 Diabetes

The activation of monocytes and macrophages plays a central role in chronic inflammation associated with type 2 diabetes mellitus (T2D) and cardiovascular disease. However, the precise epigenetic mechanisms involved are unclear. From RNA-seq analysis we found dysregulated expression of several genes, including downregulation of JARID2 in human CD14+ monocytes obtained from T2D patients versus controls. JARID2 protein functions as a transcription repressor by facilitating the recruitment of polycomb repressor complex 2 and associated histone H3K27-trimethylation to target genes. RT-qPCR and RNA-seq analysis showed that high glucose +TNF-α (HT) , key pathological factors in diabetes, downregulated JARID2 in human monocytes along with genes involved in inflammation and cytokine related signaling networks. Western blotting also showed HT reduces JARID2 protein levels in human monocytes. Furthermore, JARID2 knockdown with siRNAs increased proliferation and enhanced LPS and HT induced inflammatory genes in human monocytes. ATAC-seq revealed that HT increased chromatin-accessibility at promoters of inflammatory genes like IL1B that were upregulated by JARID2 knockdown. Interestingly, microRNA-seq analysis revealed that CD14+ monocytes from T2D patients showed increased expression of several microRNAs with complementarity to the JARID2 3’-UTR, indicating cross-talk between epigenetic factors and microRNA-dependent mechanisms. Mouse orthologous Jarid2 was downregulated in macrophages from diabetic db/db mice and in macrophages from normal C57BL/6 mice treated with HT, similar to human JARID2. These results demonstrate that JARID2 plays a key role in chromatin remodeling and restraining inflammatory genes in monocytes, and its downregulation in T2D can augment inflammation. Further, understanding of epigenetic regulators like JARID2 can lead to novel therapies for chronic inflammatory diabetic complications. Disclosure M.A.Reddy: None. V.S.Tanwar: None. L.Zhang: None. L.L.Lanting: None. M.Wang: None. P.Pandey: None. Z.Chen: None. X.Wu: None. R.Natarajan: None. Funding National Institutes of Health (DK065073) to RN AR-DMRI Endowment Pilot grant to MAR

Knockdown of JARID2 inhibits the proliferation and invasion of ovarian cancer through the PI3K/Akt signaling pathway.

Protein Jumonji (JARID2), a member of the family of JmjC domain-containing proteins, has been reported to serve an important role in tumor growth and metastasis. However, the expression pattern and role of JARID2 in ovarian cancer remains unclear. Therefore, in the present study, the role of JARID2 in ovarian cancer was investigated, as well as the underlying mechanisms. The results of the present study demonstrated that the expression of JARID2 is upregulated in human ovarian cancer cell lines. Furthermore, downregulation of JARID2 significantly suppressed proliferation, migration, invasion and epithelial‑mesenchymal transition in human ovarian cancer cells. Mechanistically, downregulation of JARID2 decreased the protein expression levels of phosphorylated phosphoinositide 3‑kinase (PI3K) and protein kinase B (Akt) in ovarian cancer cells. In conclusion the observations suggested that knockdown of JARID2 inhibited proliferation, migration and invasion invitro through the inactivation of the PI3K/Akt signaling pathway. Therefore, JARID2 may represent a potential therapeutic target for the treatment of ovarian cancer.

Knockdown of JARID2 inhibits the viability and migration of placenta trophoblast cells in preeclampsia.

Protein Jumonji (JARID2) is a member of the Jumonji family of proteins and has been demonstrated to regulate cell proliferation and invasion. However, little is known about the role of JARID2 in the metastasis of placenta trophoblast cells. In the present study, the effect and the underlying molecular mechanism of JARID2 on trophoblast cell viability and invasion was investigated. The expression of JARID2 in placental tissues was analyzed by reverse transcription‑quantitative polymerase chain reaction and western blotting. HTR8/SVneo cells were transfected with si‑JARID2 or scramble for 24h. Cell viability, migration and invasion in HTR8/SVneo cells were then evaluated. The expression levels of matrix metallopeptidase 2 (MMP2), MMP9, phosphorylated phosphatidylinositol 3‑kinase (p‑PI3K), PI3K, phosphorylated AKT serine/threonine kinase 1 (p‑Akt) and Akt in HTR8/SVneo cells were also detected using western blotting. The results of the present study demonstrated that JARID2 is underexpressed in human preeclamptic placentas. The knockdown of JARID2 significantly inhibited the viability, migration and invasion of HTR8/SVneo cells. In addition, the knockdown of JARID2 significantly decreased the levels of phosphorylated PI3K and Akt in HTR8/SVneo cells. The results of the present study demonstrated that JARID2 may serve a role in the progression of preeclampsia. The knockdown of JARID2 inhibited the viability and invasion of trophoblast cells in preeclampsia by suppressing the PI3K/Akt signaling pathway. Therefore, JARID2 may serve as a novel potential target for treating preeclampsia.

JARID2 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial-mesenchymal transition through PTEN/AKT signaling.

JARID2 is crucial for maintenance of pluripotency and differentiation of embryonic stem cells. However, little is known about the role of JARID2 in metastasis of hepatocellular carcinoma (HCC). This study found that JARID2 expression was significantly higher in HCC tissues than that in adjacent non-tumor liver tissues (ANLTs), and its expression level correlated with HCC metastasis. High JARID2 expression was significantly correlated with multiple tumor nodules, high Edmondson-Steiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05) and indicated poor prognosis of HCC in training and validation cohorts (all P < 0.05) totaling 182 patients. High JARID2 expression was an independent and significant risk factor for disease-free survival (DFS; P = 0.017) and overall survival (OS; P = 0.041) after curative liver resection in training cohort, and also validated as an independent and significant risk factor for DFS (P = 0.033) and OS (P = 0.031) in validation cohort. Moreover, down-regulation of JARID2 dramatically inhibited HCC cell migration, invasion, proliferation in vitro and metastasis in vivo, whereas overexpression of JARID2 significantly increased migration, invasion, proliferation in vitro and metastasis in vivo. Mechanistically, the data showed that JARID2 exerted its function by repressing PTEN expression through increasing H3K27 trimethylation (H3K27me3) at PTEN promoter region, which subsequently resulted in activation of protein kinase B (AKT) and enhanced epithelial-mesenchymal transition (EMT). In conclusion, this study revealed that JARID2 promotes invasion and metastasis of HCC by facilitating EMT through PTEN/AKT signaling.

Interactions between JARID2 and Noncoding RNAs Regulate PRC2 Recruitment to Chromatin

JARID2 is an accessory component of Polycomb repressive complex-2 (PRC2) required for the differentiation of embryonic stem cells (ESCs). A role for JARID2 in the recruitment of PRC2 to target genes silenced during differentiation has been put forward, but the molecular details remain unclear. We identified a 30-amino-acid region of JARID2 that mediates interactions with long noncoding RNAs (lncRNAs) and found that the presence oflncRNAs stimulated JARID2-EZH2 interactions invitro and JARID2-mediated recruitment of PRC2 to chromatin invivo. Native and crosslinked RNA immunoprecipitations of JARID2 revealed that Meg3 and other lncRNAs from the imprinted Dlk1-Dio3 locus, an important regulator of development, interacted with PRC2 via JARID2. Lack of MEG3 expression in human induced pluripotent cells altered the chromatin distribution of JARID2, PRC2, and H3K27me3. Our findings show that lncRNAs facilitate JARID2-PRC2 interactions on chromatin and suggest a mechanism by which lncRNAs contribute to PRC2 recruitment.

A Possible Role for JARID2 in Cleft Lip and Palate

A Possible Role for JARID2 in Cleft Lip and Palate

Jarid2 is among a set of genes differentially regulated by Nkx2.5 during outflow tract morphogenesis

Nkx2.5, a transcription factor implicated in human congenital heart disease, is required for regulation of second heart field (SHF) progenitors contributing to outflow tract (OFT). Here, we define a set of genes (Lrrn1, Elovl2, Safb, Slc39a6, Khdrbs1, Hoxb4, Fez1, Ccdc117, Jarid2, Nrcam, and Enpp3) expressed in SHF containing pharyngeal arch tissue whose regulation is dependent on Nkx2.5. Further investigation shows that Jarid2, which has been implicated in OFT morphogenesis, is a direct target of Nkx2.5 regulation. Jarid2 expression was up-regulated in SHF mesoderm of Nkx2.5-deficient embryos. Chromatin immunoprecipitation analysis showed Nkx2.5 interaction with consensus binding sites in the Jarid2 promoter in pharyngeal arch cells. Finally, Jarid2 promoter activity and mRNA expression levels were down-regulated by Nkx2.5 overexpression. Given the role of Jarid2 as a regulator of early cardiac proliferation, these findings highlight Jarid2 as one of several potential mediators of the critical role played by Nkx2.5 during OFT morphogenesis.