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The critical importance of epigenetics in autoimmune-related skin diseases

Frontiers of Medicine 2023, Volume 17, Issue 1,   Pages 43-57 doi: 10.1007/s11684-022-0980-8

Abstract: Epigenetics is the study of heritable mechanisms that regulate gene expression without changing DNA sequencesfindings will expand our understanding and highlight the possible clinical applications of precision epigenetics

Keywords: epigenetics     autoimmune-related skin diseases     DNA methylation     histone modifications     noncoding RNAs    

Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

Frontiers of Medicine 2021, Volume 15, Issue 3,   Pages 383-403 doi: 10.1007/s11684-020-0818-1

Abstract: Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

Keywords: moonlighting function     tumor metabolism     epigenetics    

Characterization of chromatin accessibility in psoriasis

Frontiers of Medicine 2022, Volume 16, Issue 3,   Pages 483-495 doi: 10.1007/s11684-021-0872-3

Abstract: The pathological hallmarks of psoriasis involve alterations in T cell genes associated with transcriptional levels, which are determined by chromatin accessibility. However, to what extent these alterations in T cell transcriptional levels recapitulate the epigenetic features of psoriasis remains unknown. Here, we systematically profiled chromatin accessibility on Th1, Th2, Th1-17, Th17, and Treg cells and found that chromatin remodeling contributes significantly to the pathogenesis of the disease. The chromatin remodeling tendency of different subtypes of Th cells were relatively consistent. Next, we profiled chromatin accessibility and transcriptional dynamics on memory Th/Treg cells. In the memory Th cells, 803 increased and 545 decreased chromatin-accessible regions were identified. In the memory Treg cells, 713 increased and 1206 decreased chromatin-accessible regions were identified. A total of 54 and 53 genes were differentially expressed in the peaks associated with the memory Th and Treg cells. FOSL1, SPI1, ATF3, NFKB1, RUNX, ETV4, ERG, FLI1, and ETC1 were identified as regulators in the development of psoriasis. The transcriptional regulatory network showed that NFKB1 and RELA were highly connected and central to the network. NFKB1 regulated the genes of CCL3, CXCL2, and IL1RN. Our results provided candidate transcription factors and a foundational framework of the regulomes of the disease.

Keywords: psoriasis     ATAC-seq     epigenetics     transcription factor    

Non-genetic mechanisms of diabetic nephropathy

Qiuxia Han, Hanyu Zhu, Xiangmei Chen, Zhangsuo Liu

Frontiers of Medicine 2017, Volume 11, Issue 3,   Pages 319-332 doi: 10.1007/s11684-017-0569-9

Abstract: inflammation response, epithelial–mesenchymal transition, apoptosis and mitochondrial damage, epigenetics

Keywords: nephropathy     immune inflammatory response     epithelial–mesenchymal transition     apoptosis     mitochondrial damage     epigenetics    

Pharmacogenomics can improve antipsychotic treatment in schizophrenia

Qingqing Xu, Xi Wu, Yuyu Xiong, Qinghe Xing, Lin He, Shengying Qin

Frontiers of Medicine 2013, Volume 7, Issue 2,   Pages 180-190 doi: 10.1007/s11684-013-0249-3

Abstract: the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics

Keywords: pharmacogenomics     epigenetics     schizophrenia     antipsychotics    

The value of epigenetic markers in esophageal cancer

Xiao-Mei ZHANG, Ming-Zhou GUO,

Frontiers of Medicine 2010, Volume 4, Issue 4,   Pages 378-384 doi: 10.1007/s11684-010-0230-3

Abstract: Developing esophageal cancer is a multi-step process that begins with the accumulation of genetic and epigenetic alterations, and leads to the activation of oncogenes and the inactivation or loss of tumor suppressor genes (TSG). In addition to genetic alteration, epigenetic modifications, and in particular DNA methylation, are recognized as a common molecular alteration in human tumors. In esophageal cancer, aberrant methylation of promoter regions occurs not only in advanced cancer, but also in premalignant lesions. DNA methylation is related to survival time and sensitivity of chemoradiotherapy. This review is mainly focused on epigenetic changes in esophageal cancer and the value of early detection for patient prognosis, treatment choices, and potential targeting therapy.

Keywords: epigenetics     DNA methylation     esophageal cancer     dysplasia    

RNA m6A modification and its function in diseases

Jiyu Tong, Richard A. Flavell, Hua-Bing Li

Frontiers of Medicine 2018, Volume 12, Issue 4,   Pages 481-489 doi: 10.1007/s11684-018-0654-8

Abstract:

N6-methyladenosine (m6A) is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism. m6A modification could be installed by m6A “writers” composed of core catalytic components (METTL3/METTL14/WTAP) and newly defined regulators and removed by m6A “erasers” (FTO and ALKBH5). The function of m6A is executed by m6A “readers” that bind to m6A directly (YTH domain-containing proteins, eIF3 and IGF2BPs) or indirectly (HNRNPA2B1). In the past few years, advances in m6A modulators (“writers,” “erasers,” and “readers”) have remarkably renewed our understanding of the function and regulation of m6A in different cells under normal or disease conditions. However, the mechanism and the regulatory network of m6A are still largely unknown. Moreover, investigations of the m6A physiological roles in human diseases are limited. In this review, we summarize the recent advances in m6A research and highlight the functional relevance and importance of m6A modification in in vitro cell lines, in physiological contexts, and in cancers.

Keywords: RNA modification     m6A     immunity     cancer     epigenetics    

Epigenetic dysregulation in hepatocellular carcinoma: focus on polycomb group proteins

Sandy Leung-Kuen Au, Irene Oi-Lin Ng, Chun-Ming Wong

Frontiers of Medicine 2013, Volume 7, Issue 2,   Pages 231-241 doi: 10.1007/s11684-013-0253-7

Abstract:

Hepatocellular carcinoma (HCC) development is characterized by the presence of epigenetic alterations, including promoter DNA hypermethylation and post-translational modifications of histone, which profoundly affect expression of a wide repertoire of genes critical for cancer development. Emerging data suggest that deregulation of polycomb group (PcG) proteins, which are key chromatin modifiers repressing gene transcription during developmental stage, plays a causative role in oncogenesis. PcG proteins assemble into polycomb repressive complex 1 (PRC1) and polycomb repressive complex 2 (PRC2) to impose the histone H3 lysine 27 trimethylation (H3K27me3) modification for repression. In this review, we will first recapitulate the mechanisms of two key epigenetic pathways: DNA methylation and histone modifications. Specifically, we will focus our discussion on the molecular roles of PcG proteins. Next, we will highlight recent findings on PcG proteins, their clinicopathological implication and their downstream molecular consequence in hepatocarcinogenesis. Last but not least, we will consider the therapeutic potential of targeting enhancer of zeste homolog 2 (EZH2) as a possible treatment for HCC. Improving our understanding on the roles of PcG proteins in hepatocarcinogenesis can benefit the development of epigenetic-based therapy.

Keywords: liver cancer     epigenetics     histone modifications     polycomb group proteins     enhancer of zeste homolog 2 (EZH2    

Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer

Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu

Frontiers of Medicine 2020, Volume 14, Issue 1,   Pages 60-67 doi: 10.1007/s11684-019-0694-8

Abstract: Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

Keywords: BPTF     small molecule     epigenetics     non-small-cell lung cancer    

Transcription Factors HNF1A, HNF4A, and FOXA2 Regulate Hepatic Cell Protein N-Glycosylation Article

Vedrana Vičić Bočkor,Nika Foglar,Goran Josipović,Marija Klasić,Ana Vujić,Branimir Plavša,Toma Keser,Samira Smajlović,Aleksandar Vojta,Vlatka Zoldoš

Engineering 2024, Volume 32, Issue 1,   Pages 58-69 doi: 10.1016/j.eng.2023.09.019

Abstract:

Hepatocyte nuclear factor 1 alpha (HNF1A), hepatocyte nuclear factor 4 alpha (HNF4A), and forkhead box protein A2 (FOXA2) are key transcription factors that regulate a complex gene network in the liver, creating a regulatory transcriptional loop. The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes. Our in silico analysis of HNF1A, HNF4A, and FOXA2 binding to the 10 candidate glyco-genes studied in this work confirms a significant enrichment of these transcription factors specifically in the liver. Our previous studies identified HNF1A as a master regulator of fucosylation, glycan branching, and galactosylation of plasma glycoproteins. Here, we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype. We used the state-of-the-art clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9) molecular tool for the downregulation of the HNF1A, HNF4A, and FOXA2 genes in HepG2 cells—a human liver cancer cell line. The results show that the downregulation of all three genes individually and in pairs affects the transcriptional activity of many glyco-genes, although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures. The effect is better seen as an overall change in the total HepG2 N-glycome, primarily due to the extension of biantennary glycans. We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure. We also propose a model showing feedback loops with the mutual activation of HNF1A–FOXA2 and HNF4A–FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.

Keywords: Clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9)     Epigenetics     Hepatocyte    

Title Author Date Type Operation

The critical importance of epigenetics in autoimmune-related skin diseases

Journal Article

Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

Journal Article

Characterization of chromatin accessibility in psoriasis

Journal Article

Non-genetic mechanisms of diabetic nephropathy

Qiuxia Han, Hanyu Zhu, Xiangmei Chen, Zhangsuo Liu

Journal Article

Pharmacogenomics can improve antipsychotic treatment in schizophrenia

Qingqing Xu, Xi Wu, Yuyu Xiong, Qinghe Xing, Lin He, Shengying Qin

Journal Article

The value of epigenetic markers in esophageal cancer

Xiao-Mei ZHANG, Ming-Zhou GUO,

Journal Article

RNA m6A modification and its function in diseases

Jiyu Tong, Richard A. Flavell, Hua-Bing Li

Journal Article

Epigenetic dysregulation in hepatocellular carcinoma: focus on polycomb group proteins

Sandy Leung-Kuen Au, Irene Oi-Lin Ng, Chun-Ming Wong

Journal Article

Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer

Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu

Journal Article

Transcription Factors HNF1A, HNF4A, and FOXA2 Regulate Hepatic Cell Protein N-Glycosylation

Vedrana Vičić Bočkor,Nika Foglar,Goran Josipović,Marija Klasić,Ana Vujić,Branimir Plavša,Toma Keser,Samira Smajlović,Aleksandar Vojta,Vlatka Zoldoš

Journal Article