Polyubiquitination of the demethylase Jhd2 controls histone methylation and gene expression

The identification of histone methyltransferases and demethylases has uncovered a dynamic methylation system needed to modulate appropriate levels of gene expression. Gene expression levels of various histone demethylases, such as the JARID1 family, show distinct patterns of embryonic and adult expression and respond to different environmental cues, suggesting that histone demethylase protein levels must be tightly regulated for proper development. In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome. We determine that polyubiquitin-mediated degradation of Jhd2 controls in vivo H3 K4 trimethylation and gene expression levels. Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression.     

Epigenetic modulation of macrophage polarization- perspectives in diabetic wounds

Diabetes is a chronic metabolic disorder that poses a global burden to healthcare. Increasing incidence of diabetes-related complications in the affected population includes a delay in wound healing that often results in non-traumatic limb amputations. Owing to the intricacies of the healing process and crosstalk between the multitude of participating cells, the identification of hyperglycaemia-induced changes at both cellular and molecular levels poses a challenge. Macrophages are one of the key participants in wound healing and continue to exert functional changes at the wound site since the time of injury. In the present review, we discuss the role of these cells and their aberrant functions in diabetic wounds. We have extensively studied the process of macrophage polarization (MP) and its modulation through epigenetic modifications. Data from both pre-clinical and clinical studies on diabetes have co-related hyperglycaemia induced changes in gene expression to an increased incidence of diabetic complications. Hyperglycaemia and oxidative stress, create an environment prone to changes in the epigenetic code, that is manifested as an altered inflammatory gene expression. Here, we have attempted to understand the different epigenetic modulations that possibly contribute towards dysregulated MP, resulting in delayed wound healing.     

组蛋白去甲基化酶Jmjd3对牙髓干细胞成牙本质向分化的影响研究

目的研究组蛋白去甲基化酶Jmjd3对牙髓干细胞(dental pulp stem cells,DPSCs)成牙本质向分化的影响。方法原代分离培养DPSCs,用流式细胞术和茜素红染色鉴定DPSCs。体外诱导DPSCs成牙本质向分化不同时间(0、3、5、7、14 d),qRT-PCR检测Jmjd3及成牙本质细胞标志物牙本质涎磷蛋白(dentin sialophosphoprotein,DSPP)、牙本质基质蛋白1(dentin matrix protein1,DMP1)的表达情况。用不同浓度(0、1、10μmol/L)的Jmjd3抑制剂GSK-J4处理DPSCs 14 d,q RT-PCR检测DSPP、DMP1的表达情况。结果原代培养的DPSCs表达间充质干细胞表面标记物CD44、CD29、CD146,体外诱导培养具有成骨分化潜能。DPSCs成牙本质向分化过程中,Jmjd3、DSPP、DMP1表达水平均上调(P<0.05),且可能具有时间依赖性。10μmol/L GSK-J4处理DPSCs可明显抑制DSPP、DMP1的表达(P<0.05)。结论Jmjd3在DPSCs成牙本质向分化过程中发挥正调节作用,且与其去甲基化酶活性相关。     

Design and Synthesis of Novel Pyrazino[2,1‐a]isoquinolin Derivatives with Potent Antifungal Activity

A series of novel pyrazino[2,1‐a]isoquinolin compounds were designed, synthesized, and their antifungal activities in vitro were evaluated. The results showed that all of the title compounds exhibited antifungal activities. Most of them exhibited stronger antifungal activities than the lead compounds; compound 7c is more potent than fluconazole against two of the three tested fungal strains. The studies presented here provide a new structural type for the development of novel antifungal agents.     

LSD1在肿瘤中的研究进展及其抑制剂的开发现状

在肿瘤的发生、发展过程中,遗传物质的异常改变发挥了重要作用,但随着表观遗传学的出现,改变了人类对遗传信息的认知,表观遗传学逐渐成为肿瘤研究领域中的热点。组蛋白去甲基化酶1(LSD1)是第1个被发现的组蛋白去甲基化酶,依赖于FAD的单胺氧化酶,可以催化组蛋白赖氨酸H3K4和H3K9去甲基化,启动或抑制基因的转录。目前研究证实,LSD1在多种肿瘤中高表达并与肿瘤的发生及预后密切相关。LSD1对肿瘤的增殖、侵袭和转移起重要的调控作用,因此逐渐成为潜在的抗肿瘤靶点。本文将对LSD1在肿瘤领域的研究进展及其抑制剂在肿瘤中的应用作一综述。     

The Dynamics of HCF-1 Modulation of Herpes Simplex Virus Chromatin during Initiation of Infection

Successful infection of herpes simplex virus is dependent upon chromatin modulation by the cellular coactivator host cell factor-1 (HCF-1). This review focuses on the multiple chromatin modulation components associated with HCF-1 and the chromatin-related dynamics mediated by this coactivator that lead to the initiation of herpes simplex virus (HSV) immediate early gene expression.