虚拟专刊 | Virtual Issue on Epigenetics

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More than just a histone deacetylase: cytoplasmic SIRT6 facilitates fatty acid oxidation through ACSL5 deacetylation

Shuoshuo Li, Zengqiang Yuan.

Acta Biochim Biophys Sin 2023, 55: 525-527.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, ranging from hepatic steatosis and nonalcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, and even leading to hepatocellular carcinoma. The pathogenesis of NAFLD is complex. It was suggested that cytoplasmic SIRT6 is involved in NAFLD progression by regulating FFA metabolism.

• SIRT6 translocates to the cytoplasm in response to palmitic acid treatment. 

• SIRT6-mediated ACSL5 deacetylation promotes lipid expenditure through fatty aid oxidation.

• Perturbation of the SIRT6–ACSL5 axis contributes to the progression from simple steatosis to steatohepatosis. 

Cooperation between NSPc1 and DNA methylation represses HOXA11 expression and promotes apoptosis of trophoblast cells during preeclampsia

Lin Xie, Ning Ding, Siqi Sheng, Honghong Zhang, He Yin, Lina Gao, Hui Zhang, Shengchao Ma, Anning Yang, Guizhong Li, Yun Jiao, Qing Shi, Yideng Jiang, Huiping Zhang.

Acta Biochim Biophys Sin 2023, 55: 202-214.

Apoptosis is important in placental development and it is also involved in the pathophysiology of preeclampsia. Here, we show that the interaction between DNMT3a and NSPc1 promotes the binding of DNMT3a to HOXA11 promoter, thus represses HOXA11 expression and promotes trophoblast cells apoptosis during preeclampsia.

• NSPc1 is upregulated in trophoblast cells and promotes apoptosis of trophoblast cells during preeclampsia.

• NSPc1 specifically represses HOXA11 expression during apoptosis of trophoblast cells in preeclampsia.

• NSPc1 promotes DNMT3a binding to HOXA11 promoter to repress HOXA11 expression.

The pseudogene DUXAP10 contributes to gefitinib resistance in NSCLC by repressing OAS2 expression

Shengnan Ren, Ya Zhu, Siying Wang, Qinqiu Zhang, Niu Zhang, Xiaoteng Zou, Chenchen Wei, Zhaoxia Wang.

Acta Biochim Biophys Sin 2023, 55: 81-90.

Gefitinib-resistance is one of the major causes of therapeutic failure in advanced EGFR mutant lung cancer. However, the expression patterns and potential biologic functions of DUXAP10 in gefitinib resistance are still unknown. In this study, we evaluated the expression patterns and potential biological functions of the pseudogene DUXAP10 in gefitinib resistance.

• Pseudogene DUXAP10 expression is significantly upregulated in the NSCLC gefitinib-resistant cells and tissues.

• Gain and loss function assays show that knockdown of DUXAP10 reverses gefitinib resistance both in vitro and in vivo.

• DUXAP10 could interact with histone methyltransferase EZH2 to repress the expression of OAS2. The DUXAP10/EZH2/OAS2 axis might be a promising therapeutic target to overcome acquired gefitinib resistance in NSCLC.

LncRNA FPASL suppresses fibroblast proliferation through its DNA methylation via DNMT3b in hypertrophic scar

Kai Wu, Fang Ma, Jiangyong Shen, Hui Zhang, Yu Wan, Xi He, Anning Yang, Jiantuan Xiong, Yun jiao, Zhigang Bai, Shengchao Ma, Yideng Jiang, Huiping Zhang, Yinju Hao.

Acta Biochim Biophys Sin 2022, 54: 1854-1862.

Excessive proliferation of fibroblasts is a hallmark of hypertrophic scar. Some studies suggest that long noncoding RNAs (lncRNAs) have been implicated in fibroblast proliferation in hypertrophic scar. Here, we investigate that DNMT3b-mediated lncRNA FPASL (fibroblast proliferation-associated LncRNA) promoter hypermethylation leads to downregulation of FPASL expression in hypertrophic scar. FPASL inhibits the fibroblast proliferation and G1/S cell cycle transition.

• The novel lncRNA FPASL suppresses fibroblast proliferation and induces the G0/G1 phase cell cycle arrest in hypertrophic scar.

• DNMT3b is significantly increased and involved in epigenetic regulation of FPASL promoter in hypertrophic scar.

• DNMT3b mediates FPASL-regulated fibroblast proliferation and cell cycle progressions in hypertrophic scar.

Extracellular-superoxide dismutase DNA methylation promotes oxidative stress in homocysteine-induced atherosclerosis

Shengchao Ma, Guanjun Lu, Qing Zhang, Ning Ding, Yuzhen Jie, Hui Zhang, Lingbo Xu, Lin Xie, Xiaoling Yang, Huiping Zhang, Yideng Jiang.

Acta Biochim Biophys Sin 2022, 54: 1222-1233.

Homocysteine (Hcy)-induced oxidative stress is an important factor in the occurrence and development of atherosclerosis (AS), which is an independent risk factor for the development of AS. The promoter DNA methylation of extracellular superoxide dismutase (EC-SOD) is regulated the expression of EC-SOD, which is responsible for the imbalance of oxidation and antioxidant in development of AS induced by Hcy. Our results show that DNMT1 mediates EC-SOD promoter hypomethylation to suppress its expression, and thus promoting oxidative stress and AS induced by Hcy.

• EC-SOD expression is suppressed by Hcy to elevate superoxide anion, thus promoting the formation of atherogenic lesions.

• The efficiency of transfer of methyl groups from SAM to the numerous methyl acceptors is significantly decreased, thus leading to EC-SOD hypomethylation. 

• DNMT1 is significantly increased and involved in epigenetic regulation process of EC-SOD promoter in aorta of ApoE‒/‒ mice induced by Hcy.

TMEM106A transcriptionally regulated by promoter methylation is involved in invasion and metastasis of hepatocellular carcinoma

Shiming Shi, Biao Wang, Jinglei Wan, Lina Song, Guiqi Zhu, Junxian Du, Luxi Ye, Qianqian Zhao, Jialiang Cai, Qing Chen, Kun Xiao, Jian He, Lei Yu, Zhi Dai.

Acta Biochim Biophys Sin 2022, 54: 1008-1020.

Hepatocellular carcinoma (HCC) is the most common cancer worldwide with an extremely poor prognosis. Transmembrane protein 106A (TMEM106A) has been reported to be dysregulated in several types of cancers. In this study, we find that TMEM106A is markedly downregulated in HCC compared with that in normal liver tissue and HCC patients with TMEM106A hypermethylation have a poor clinical prognosis. Functional studies reveal the molecular mechanism of how TMEM106A regulates HCC.

• Tumor-specific DNA methylation of TMEM106A is frequently observed in tumor tissues from HCC patients. Downregulation of TMEM106A protein expression has a strong relationship with TMEM106A methylation.

• Overexpression of TMEM106A significantly suppresses the malignant behavior of HCC cells in vitro and decreases tumorigenicity and lung metastasis in vivo.

• TMEM106A inhibits epithelial-mesenchymal transition (EMT) of HCC cells through inactivating  the ERK1/2/Slug signaling pathway.

Involvement of PGC7 and UHRF1 in the regulation of DNA methylation of the IG-DMR in the imprinted Dlk1-Dio3 locus

Mengying Yu, Yingxiang Liu, Zhuo Han, Wei Du, Bingxue Chen, Lei Zhang, Hongni Xue, Zihan Zhang, Zekun Guo.

Acta Biochim Biophys Sin 2022, 54: 917-930.

The expression level of Gtl2, a non-coding transcript originating from the Dlk1-Dio3 cluster which is critical for cell growth and development, is considered as the only reliable marker to distinguish low-grade and high-grade iPSCs. The DNA methylation state of the IG-DNA methylated regions (DMR), which is located upstream of the Gtl2 gene, dominantly contributes to the control of gene expression in the Dlk1-Dio3 locus. Here, we reveal that DNA hypermethylation in the IG-DMR in F9 ECs is induced by the interaction between PGC7 and UHRF1, which leads to recruitment of both DNMT1 and DNMT3A to this region.

• PGC7 and UHRF1 cooperatively bound in the IG-DMR and PGC7 promote the recruitment of DNMT1 by UHRF1 to maintain DNA methylation in the IG-DMR locus.

• The interaction between PGC7 and UHRF1 also strengthens their binding to H3K9me3 and leads to further enrichment of H3K9me3 in the IG-DMR by recruiting the specific histone methyltransferase SETDB1.

• The abundance of H3K9me3 promotes DNMT3A to bind to the IG-DMR and increases DNA methylation level in this region.

Epigenetics in the pathogenesis of diabetic nephropathy

Xue Li, Lihong Lu, Wenting Hou, Ting Huang, Xiangyuan Chen, Jie Qi, Yanjun Zhao, Minmin Zhu.

Acta Biochim Biophys Sin 2022, 54: 163-172.

Diabetic nephropathy (DN), as a microvascular complication with high incidence in diabetic patients, greatly increases the mortality of patients. The occurrence of diabetic nephropathy is caused by various factors. The present review mainly discusses the role of epigenetics in diabetic nephropathy.

• Epigenetic modification, including DNA methylation, histone modification and non-coding RNA regulation, has an important influence on the development of diabetic nephropathy.

• DNA methylation and histone modification can regulate each other. Moreover, their specific inhibitors could hinder the progression of diabetic nephropathy.

• Non-coding RNAs regulate the expressions of genes at the post-transcription and translation levels, which not only is implicated in the development of diabetic nephropathy, but also plays an important role in controlling DNA methylation and histone modification.

Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice

Ling Shi, Xuexin Jin, Zheng Li, Rui Gong, Yang Guo, Jiudong Ma, Yang Zhang, Benzhi Cai, Baofeng Yang, Dongmei Gong, Zhenwei Pan.

Acta Biochim Biophys Sin 2022, 54: 199-208.

Methyltransferase-like 3 (Mettl3) is a component of methyltransferase complex that mediates m6A modification of RNAs, and participates in multiple biological processes. However, the role of Mettl3 in cardiac electrophysiology remains unknown. This study aims to explore the ventricular arrhythmia susceptibility of Mettl3+/– mice and the underlying mechanisms.

• The role of m6A modification in the regulation of cardiac electrophysiology is proposed.
  

• The mechanism of Mettl3 deficiency increases ventricular arrhythmia susceptibility relies on the upregulation of Cav1.2 by reducing m6A modification on CACNA1C mRNA in mice.

• m6A methylation might represent a new mechanism in the regulation of cardiac ionic homeostasis and the development of arrhythmia.

miR-30a-5p promotes glomerular podocyte apoptosis via DNMT1-mediated hypermethylation under hyperhomocysteinemia

Ning Ding, Lin Xie, Fei Ma, Shengchao Ma, Jiantuan Xiong, Guanjun Lu, Huiping Zhang, Yideng Jiang.

Acta Biochim Biophys Sin 2022, 54: 1222-1233.

Abnormal elevation of homocysteine (Hcy) level is closely related to the development and progression of chronic kidney disease (CKD), with the molecular mechanisms that are not fully elucidated. Given the demonstration that miR-30a-5p is specifically expressed in glomerular podocytes, we aimed to investigate the role and potential underlying mechanism of miR-30a-5p in glomerular podocyte apoptosis induced by Hcy. 

• miR-30a-5p directly targets the 3′-UTR of FOXA1 and overexpression of miR-30a-5p inhibits FOXA1 expression. 

• DNMT1 is the key regulator of miR-30a-5p, which in turn enhances miR-30a-5p promoter methylation level and thereby inhibits its expression. 

• Epigenetic modification of miR-30a-5p is involved in glomerular podocyte injury induced by Hcy.

N6-methyladenosine demethylase ALKBH5: a novel regulator of proliferation and differentiation of chicken preadipocytes

Qi Zhang, Bohan Cheng, Haixu Jiang, Huili Zhang, Hui Li.

Acta Biochim Biophys Sin 2022, 54: 55-63.

Previous studies have reported that the N6-methyladenosine demethylase ALKBH5 can regulate adipogenesis in humans. However, its function in birds remains unclear. In this study we aimed to explore the expression and function of the ALKBH5 gene in chicken adipose tissue. Our results indicated that ALKBH5 is a novel regulator of proliferation and differentiation of chicken preadipocytes.

• ALKBH5 is widely expressed in various chicken tissues, and the expression of ALKBH5 is relatively higher in abdominal adipose tissue. 

• the proliferation and differentiation of preadipocytes are associated with reduced and increased expression of ALKBH5, respectively. 

• ALKBH5 knockout promotes preadipocyte proliferation, as evidenced by an increase in cell viability, DNA replication activity, G1-S cell cycle progression, and the expressions of Ki67 and PCNA.

• after knockout of ALKBH5, the lipid droplet accumulation and the expression of PPARγ, A-FABP, and FAS are reduced significantly.