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表观遗传修饰是指在不改变DNA序列的情况下, 基因表达发生的可遗传变化. 5-羟甲基胞嘧啶(5-hydroxymethylcytosine, 5hmC)是继5-甲基胞嘧啶(5-methylcytosine, 5mC)后发现的表观遗传修饰, 被称为“第六种碱基”. 5hmC广泛分布于哺乳动物的组织和细胞中, 它的异常表达与肿瘤发生、发育性疾病和神经系统疾病密切相关. 由于5hmC的结构与5mC相似, 并且其丰度远远低于5mC, 传统方法难以实现对5hmC的准确和灵敏检测. 近年来, 科学家们结合新的修饰方法和信号放大策略, 发展了一系列超灵敏检测5hmC的新方法, 包括液相色谱串联质谱法、荧光法、电化学法、光电化学法、单碱基分辨率的测序法和单分子检测技术. 这些方法各自具有其独特优势, 有力推动了表观遗传学的发展. 本综述总结了5hmC检测方法的最新研究进展, 并对其面临的挑战和发展趋势做了展望. 相似文献
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An extension of neo-Darwinism, termed preassembly, states that genetic material required for many complex traits, such as echolocation, was present long before emergence of the traits. Assembly of genes and gene segments had occurred over protracted time-periods within large libraries of non-coding genes. Epigenetic factors ultimately promoted transfers from noncoding to coding genes, leading to abrupt formation of the trait via de novo genes. This preassembly model explains many observations that to this present day still puzzle biologists: formation of super-complexity in the absence of multiple fossil precursors, as with bat echolocation and flowering plants; major genetic and physical alterations occurring in just a few thousand years, as with housecat evolution; lack of precursors preceding lush periods of species expansion, as in the Cambrian explosion; and evolution of costly traits that exceed their need during evolutionary times, as with human intelligence. What follows in this paper is a mechanism that is not meant to supplant neo-Darwinism; instead, preassembly aims to supplement current ideas when complexity issues leave them struggling. 相似文献
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Dr. David J. Fallon Stephanie Lehmann Dr. Chun-wa Chung Alex Phillipou Dr. Christian Eberl Ken G. M. Fantom Dr. Francesca Zappacosta Dr. Vipulkumar K. Patel Dr. Marcus Bantscheff Prof. Christopher J. Schofield Prof. Nicholas C. O. Tomkinson Dr. Jacob T. Bush 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(71):17880-17888
We present a one-step Ugi reaction protocol for the expedient synthesis of photoaffinity probes for live-cell MS-based proteomics. The reaction couples an amine affinity function with commonly used photoreactive groups, and a variety of handle functionalities. Using this technology, a series of pan-BET (BET: bromodomain and extra-terminal domain) selective bromodomain photoaffinity probes were obtained by parallel synthesis. Studies on the effects of photoreactive group, linker length and irradiation wavelength on photocrosslinking efficiency provide valuable insights into photoaffinity probe design. Optimal probes were progressed to MS-based proteomics to capture the BET family of proteins from live cells and reveal their potential on- and off-target profiles. 相似文献
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Storm Hassell-Hart Sarah Picaud Raphael Lengacher Joshua Csucker Regis Millet Gilles Gasser Roger Alberto Hannah Maple Robert Felix Zbigniew J. Leśnikowski Helen J. S. Stewart Timothy J. Chevassut Simon Morley Panagis Filippakopoulos John Spencer 《Helvetica chimica acta》2021,104(3):e2000214
A series of bulky organometallic and organic analogues of the bromodomain (BRD) inhibitor (+)-JQ1 have been prepared. The most potent, N-[(adamantan-1-yl)methyl]-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide, 2e , showed excellent potency with an KD=ca. 130 nm vs. BRD4(1) and a ca. 2-fold selectivity over BRD4(2) (KD=ca. 260 nm ). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure. 相似文献
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Alain Aguirre-Vzquez Luis A. Salazar-Olivo Xchitl Flores-Ponce Ana L. Arriaga-Guerrero Dariela Garza-Rodríguez María E. Camacho-Moll Ivn Velasco Fabiola Castorena-Torres Nidheesh Dadheech Mario Bermúdez de Len 《Molecules (Basel, Switzerland)》2021,26(7)
A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2′-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects. 相似文献
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核酸碱基的表观遗传修饰是生命体实现表观遗传功能的重要组成部分,可以直接参与调控细胞分化、基因表达等重要的生理过程。然而,核酸碱基的光稳定性会受表观遗传修饰的影响,相应的碱基可能成为紫外线诱导皮肤癌产生的重要突变位点。因此,研究表观遗传修饰对核酸碱基的光物理与光化学性质的影响具有十分重要的意义。本文综述了近年来本课题组利用超快时间光谱技术结合高精度的量子化学理论计算对一系列表观遗传修饰的核酸碱基激发态动力学性质的研究。研究表明,表观遗传修饰对碱基激发态性质的影响主要分为三个方面:显著增长ππ∗1态的寿命、引入分子内电荷转移态、有效促进单重态到三重态系间窜跃。 相似文献
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Dr. Hong Zong Dhavan Shah Katherine Selwa Ryan E Tsuchida Dr. Rahul Rattan Jay Mohan Dr. Adam B Stein James B Otis Dr. Sascha N Goonewardena 《ChemistryOpen》2015,4(3):335-341
Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer–HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer–HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer–HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer. 相似文献