Author: Wen, Xiaolian ; Hu, Baichun ; Qin, Juyue ; Wang, Jian ; Yang, Yi ; Li, Yikuan ; Wang, Yihan ; Li, Hui ; Liu, Yang ; Wang, Yutong ; Wang, Chenxiao

The methylation and demethylation of lysine and arginine side chains are fundamental processes in gene regulation and disease development. Histone lysine methylation, controlled by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), plays a vital role in maintaining cellular homeostasis and has been implicated in diseases such as cancer and aging. This study focuses on two members of the lysine demethylase (KDM) family, KDM4E and KDM6B, which are significant in gene regulation and disease pathogenesis. KDM4E demonstrates selectivity for gene regulation, particularly concerning cancer, while KDM6B is implicated in inflammation and cancer. The study utilizes specific inhibitors, DA-24905 and GSK-J1, showcasing their exceptional selectivity for KDM4E and KDM6B, respectively. Employing an array of computational simulations, including sequence alignment, molecular docking, dynamics simulations, and free energy calculations, we conclude that although the binding cavities of KDM4E and KDM6B has high similarity, there are still some different crucial amino acid residues, indicating diverse binding forms between protein and ligands. Various interaction predominates when proteins are bound to different ligands, which also has significant effect on selective inhibition. These findings provide insights into potential therapeutic strategies for diseases by selectively targeting these KDM members.

01 Sep 2022·International Immunopharmacology

JMJD3/H3K27me3 epigenetic modification regulates Th17/Treg cell differentiation in ulcerative colitis

Article

Author: Gao, Fei ; Fan, Heng ; Yang, Jia ; Cheng, Bing-Jie ; He, Hong-Xia ; Yu, Ting ; Zhu, Feng ; Leng, Xue-Yuan ; Liu, Yu-Jin ; Chen, Qian-Yun

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease characterized by chronic inflammation and ulceration of the colonic mucosa, frequent relapse, and cancerization that is difficult to cure. In recent years, the incidence of UC has increased. However, its etiology and pathogenesis are still not completely clear. In this study, dextran sodium sulfate (DSS) was used to induce the model, and GSK-J1 and dexamethasone were administered to the mice. A variety of molecular biology and immunological techniques, such as immunofluorescence, PCR and chromatin immunoprecipitation (ChIP), were used to examine JMJD3/H3K27me3-mediated regulation of Th17/Treg cell differentiation in UC by targeting histone modification. This study will provide an important theoretical basis for understanding the pathogenesis and potential therapeutic targets of UC.

01 Jun 2022·Journal of Biological Chemistry

The JMJD3 histone demethylase inhibitor GSK-J1 ameliorates lipopolysaccharide-induced inflammation in a mastitis model

Article

Author: Wang, Xia ; Zhou, Er-Shun ; Wu, Zhi-Kai ; Xian, Yin-Er ; Wang, Jing-Jing ; Sun, You-Peng ; Chen, Zi-Qing ; Yang, Zheng-Tao ; Fu, Yi-Wu ; Li, Pei-Xuan

Jumonji domain-containing 3 (JMJD3/KDM6B) is a histone demethylase that plays an important role in regulating development, differentiation, immunity, and tumorigenesis. However, the mechanisms responsible for the epigenetic regulation of inflammation during mastitis remain incompletely understood. Here, we aimed to investigate the role of JMJD3 in the lipopolysaccharide (LPS)-induced mastitis model. GSK-J1, a small molecule inhibitor of JMJD3, was applied to treat LPS-induced mastitis in mice and in mouse mammary epithelial cells in vivo and in vitro. Breast tissues were then collected for histopathology and protein/gene expression examination, and mouse mammary epithelial cells were used to investigate the mechanism of regulation of the inflammatory response. We found that the JMJD3 gene and protein expression were upregulated in injured mammary glands during mastitis. Unexpectedly, we also found JMJD3 inhibition by GSK-J1 significantly alleviated the severity of inflammation in LPS-induced mastitis. These results are in agreement with the finding that GSK-J1 treatment led to the recruitment of histone 3 lysine 27 trimethylation (H3K27me3), an inhibitory chromatin mark, in vitro. Furthermore, mechanistic investigation suggested that GSK-J1 treatment directly interfered with the transcription of inflammatory-related genes by H3K27me3 modification of their promoters. Meanwhile, we also demonstrated that JMJD3 depletion or inhibition by GSK-J1 decreased the expression of toll-like receptor 4 and negated downstream NF-κB proinflammatory signaling and subsequently reduced LPS-stimulated upregulation of Tnfa, Il1b, and Il6. Together, we propose that targeting JMJD3 has therapeutic potential for the treatment of inflammatory diseases.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	CN	GlaxoSmithKline (China) R&D Co., Ltd.	15 Aug 2012

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