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时间序列多组学整合分析揭示原代肝细胞体外培养去分化过程伴随非降解性泛素化修饰的增加 Article
姜正一, 孙泽宇, 欧阳晓希, 赵亚磊, 周梦豪, 王保红, 李启睿, 范林骁, 张赛男, 李兰娟
《工程（英文）》 2020年 第6卷 第11期 页码 1302-1314 doi: 10.1016/j.eng.2020.02.011
人类蛋白质N-糖基化的十二年全基因组关联研究 Review
Anna Timoshchuk, Sodbo Sharapov, Yurii S. Aulchenko
《工程（英文）》 2023年 第26卷 第7期 页码 17-31 doi: 10.1016/j.eng.2023.03.013
Most human-secreted and membrane-bound proteins have covalently attached oligosaccharide chains, or glycans. Glycosylation influences the physical and chemical properties of proteins, as well as their biological functions. Unsurprisingly, alterations in protein glycosylation have been implicated in a growing number of human diseases, and glycans are increasingly being considered as potential therapeutic targets, an essential part of therapeutics, and biomarkers. Although glycosylation pathways are biochemically well-studied, little is known about the networks of genes that guide the cell- and tissue-specific regulation of these biochemical reactions in humans in vivo. The lack of a detailed understanding of the mechanisms regulating glycome variation and linking the glycome to human health and disease is slowing progress in clinical applications of human glycobiology. Two of the tools that can provide much sought-after knowledge of human in vivo glycobiology are human genetics and genomics, which offer a powerful data-driven agnostic approach for dissecting the biology of complex traits. This review summarizes the current state of human populational glycogenomics. In Section 1, we provide a brief overview of the N-glycan's structural organization, and in Section 2, we give a description of the major blood plasma glycoproteins. Next, in Section 3, we summarize, systemize, and generalize the results from current N-glycosylation genome-wide association studies (GWASs) that provide novel knowledge of the genetic regulation of the populational variation of glycosylation. Until now, such studies have been limited to an analysis of the human blood plasma N-glycome and the N-glycosylation of immunoglobulin G and transferrin. While these three glycomes make up a rather limited set compared with the enormous multitude of glycomes of different tissues and glycoproteins, the study of these three does allow for powerful analysis and generalization. Finally, in Section 4, we turn to genes in the established loci, paying particular attention to genes with strong support in Section 5. At the end of the review, in Sections 6 and 7, we describe special cases of interest in light of new discoveries, focusing on possible mechanisms of action and biological targets of genetic variation that have been implicated in human protein N-glycosylation.
低蛋白日粮中添加亮氨酸通过雷帕霉素靶蛋白信号通路增加成年大鼠骨骼肌重量及蛋白质合成
张博, 楚丽翠, 刘宏, 谢春元, 谯仕彦, 曾祥芳
《工程（英文）》 2017年 第3卷 第5期 页码 760-765 doi: 10.1016/J.ENG.2017.03.008
低蛋白日粮会减少动物组织中蛋白质沉积，影响骨骼肌增重。本文旨在研究低蛋白日粮中添加亮氨酸对成年大鼠骨骼肌重量和蛋白质合成的影响。结果表明，在3个处理中，RL组血清亮氨酸含量最高（P < 0.05），而异亮氨酸含量最低（P < 0.05）；CON组的缬氨酸含量低于R和RL组（P < 0.05），但采食量、蛋白质合成速度和4EBP1的磷酸化高于R和RL组（P < 0.05），同时腹脂重量显著下降（P < 0.05）。与R组相比，RL组可以增加腓肠肌重量（P < 0.05），促进S6K1磷酸化（P < 0.05），增加骨骼肌蛋白质合成（P < 0.05）。本文结论如下，在成年大鼠长期采食低蛋白日粮的情况下，日粮中添加亮氨酸可以改善大鼠的生长性能，通过提高mTOR通路中S6K1磷酸化水平，促进大鼠骨骼肌蛋白质合成，抑制蛋白质降解。
代谢组扩展生物学的“旁中心法则”——对理解基因组学-糖组学-代谢组学-表观基因组学互作的意义
Albert Stuart Reece
《工程（英文）》 2023年 第26卷 第7期 页码 16-16 doi: 10.1016/j.eng.2022.07.011
The central dogma of biology holds that the transcription of DNA into RNA and the translation of RNA into proteins forms the primary axis of biological activity [1]. Following major advances in the description of the complex glycan and lipid chains that are added onto these basic building blocks, the glycome and lipidome have recently been added to this doctrine as an exciting new extension named the ‘‘paracentral dogma” [2]. However, it has been pointed out that biological systems can include many layers, which are described in modern omics technology platforms relating to both cell-intrinsic and cell-extrinsic layers of control, including metabolomic, microbiomic, immunological, epigenomic, epitranscriptomic, proteomic and phosphoproteomic layers [3].
It is well known that stem and progenitor cells have a metabolism that is based on glycolysis and glutaminolysis [4]. Although this provides less energy to the cell than oxidative phosphorylation, it suffices for these cells’ needs, since such cells are generally relatively quiescent and normally suppress energy-intensive processes such as genome duplication and transcription. Moreover, it has been shown that the high intracellular lactate levels involved in such states not only inhibits the key gatekeeper enzymes of oxidative phosphorylation (i.e., pyruvate dehydrogenase and carnitine palmitoyl acyltransferase) but also actually covalently modifies them by lactylation in order to maintain this inhibited metabolic–epigenomic state [5]. In addition, intermediate metabolism and nutrients are the source of the very extensive library of post-translational modifications to DNA, RNA, and proteins, as well as supplying cellular energy for many of the required reactions. Hence, the metabolic state locks in and reinforces the epigenomic state, and the metabolome and epigenome thereby play mutually reinforcing roles. This self-reinforcing coordination explains why it is so difficult to generate induced pluripotent cells and is a contributory explanation for why the described protocols typically have such low cellular yields.
These concepts become even more important when it is considered that cancer cells are de-differentiated, similarly rely on glycolysis and glutaminolysis, and are similarly metabolically–epigenomically–genomically synchronized. The disruption of this metabolic system is a key focus of mechanistic cancer research.
These important considerations imply that the descriptive and predictive power of the newly described ‘‘paracentral dogma” of biology may be usefully and meaningfully extended by including the metabolome, along with the genome, transcriptome, proteome, glycome, and lipidome, to describe cell-intrinsic regulation—not only in terms of another omics analytical layer but also as a fully predictive and interactive partner in the symphonic-like multilayer coordination that evidently comprises cellular regulatory layering.
靶向膜蛋白的抗体药物开发的新进展 Review
Georgina To’a Salazar, 黄子逸, 张凝艳, 张学光, 安志强
《工程（英文）》 2021年 第7卷 第11期 页码 1541-1551 doi: 10.1016/j.eng.2020.11.013
在疾病干预的众多膜蛋白靶标中，G蛋白偶联受体（GPCR）作为人体内最大的膜受体蛋白家族，成为很多药物的重要靶点，其次是离子通道、转运蛋白和激酶等膜蛋白在细胞信号转导和运输中发挥了关键作用，当前药物研发面临的挑战在于进一步发掘此类膜蛋白的潜在靶点的干预价值，开发治疗性抗体药物。鉴于特异性抗体能够识别膜蛋白的灵敏特性，以及随着基因工程技术的进步，对已有抗体进行加工改造可获得适应多个靶点蛋白的特异性抗体。然而，成功分离特异靶向膜蛋白抗体取决于一系列因素。我们更易研制和识别结构简单且具有长片段胞外区的抗体分子，但对于高难度的靶点蛋白，如GPCR和其他复杂膜蛋白往往难以得到具有活性的候选抗体。深入研究靶标膜蛋白的结构有助于推进治疗性抗体药物的开发进程。本文概述了抗体靶向复杂膜蛋白的优势和挑战，以及膜蛋白抗原制备和抗体研发策略的最新进展。
转录因子HNF1A、HNF4A和FOXA2调节肝细胞蛋白质N-糖基化 Article
Vedrana Vičić Bočkor,Nika Foglar,Goran Josipović,Marija Klasić,Ana Vujić,Branimir Plavša,Toma Keser,Samira Smajlović,Aleksandar Vojta,Vlatka Zoldoš
《工程（英文）》 2024年 第32卷 第1期 页码 58-69 doi: 10.1016/j.eng.2023.09.019
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.
关键词： Clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9) Epigenetics Hepatocyte nuclear factor 1 alpha (HNF1A) Hepatocyte nuclear factor 4 alpha (HNF4A) Forkhead box protein A2 (FOXA2) N-glycosylation HepG2 cells
中医方证代谢组学——中药效应评价的有效途径 Review
张爱华, 孙晖, 闫广利, 韩莹, 赵琦琦, 王喜军
《工程（英文）》 2019年 第5卷 第1期 页码 60-68 doi: 10.1016/j.eng.2018.11.008
有效性评价是发现中药药效物质基础、先导化合物和质量标志物的重要前提，因此急需建立一种生物学语言，将中药有效性科学地表达出来，进一步凸显中医药的实用价值。我们以证候和方剂为研究对象，建立了科学评价中药有效性的创新方法学体系——中医方证代谢组学。它将中药血清药物化学理论与代谢组学技术有机整合，在解决证候生物标记物的基础上，建立方剂药效生物评价体系，发现并确认中药药效物质基础。该策略为提高中医理论和临床实践的科学价值提供了有力支持。本文概述了中医方证代谢组学的研究策略，利用该方法揭示临床常见中医证候生物标记物及开展相关方剂的有效性评价研究，着重阐述了中药药效物质基础及质量标记物的发现。
通过鉴定关键靶标蛋白探究青蒿素抗疟机制 Article
高鹏, 王建友, 陈嘉鋆, 谷丽维, 王晨, 徐丽婷, Yin Kwan Wong, 张会敏, 徐承超, 戴凌云, 王继刚
《工程（英文）》 2023年 第31卷 第12期 页码 86-97 doi: 10.1016/j.eng.2023.06.001
温维亮,郭新宇 ,张颖,顾生浩,赵春江
《中国工程科学》 2023年 第25卷 第4期 页码 227-238 doi: 10.15302/J-SSCAE-2023.04.015
周光耀
《中国工程科学》 2001年 第3卷 第10期 页码 28-32
标题 作者 时间 类型 操作
转录因子HNF1A、HNF4A和FOXA2调节肝细胞蛋白质N-糖基化
Vedrana Vičić Bočkor,Nika Foglar,Goran Josipović,Marija Klasić,Ana Vujić,Branimir Plavša,Toma Keser,Samira Smajlović,Aleksandar Vojta,Vlatka Zoldoš
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