Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Warsaw, Poland.
Adv Exp Med Biol. 2020;1202:259-279. doi: 10.1007/978-3-030-30651-9_13.
Signal transduction pathways directly communicate and transform chromatin to change the epigenetic landscape and regulate gene expression. Chromatin acts as a dynamic platform of signal integration and storage. Histone modifications and alteration of chromatin structure play the main role in chromatin-based gene expression regulation. Alterations in genes coding for histone modifying enzymes and chromatin modifiers result in malfunction of proteins that regulate chromatin modification and remodeling. Such dysregulations culminate in profound changes in chromatin structure and distorted patterns of gene expression. Gliomagenesis is a multistep process, involving both genetic and epigenetic alterations. Recent applications of next generation sequencing have revealed that many chromatin regulation-related genes, including ATRX, ARID1A, SMARCA4, SMARCA2, SMARCC2, BAF155 and hSNF5 are mutated in gliomas. In this review we summarize newly identified mechanisms affecting expression or functions of selected histone modifying enzymes and chromatin modifiers in gliomas. We focus on selected examples of pathogenic mechanisms involving ATRX, histone methyltransferase G9a, histone acetylases/deacetylases and chromatin remodeling complexes SMARCA2/4. We discuss the impact of selected epigenetics alterations on glioma pathobiology, signaling and therapeutic responses. We assess the attempts of targeting defective pathways with new inhibitors.
信号转导途径直接沟通并转化染色质，改变表观遗传景观并调节基因表达。染色质作为信号整合和存储的动态平台。组蛋白修饰和染色质结构的改变在基于染色质的基因表达调控中起主要作用。编码组蛋白修饰酶和染色质修饰物的基因的改变导致调节染色质修饰和重塑的蛋白质功能失常。这种失调最终导致染色质结构的深刻变化和基因表达模式的扭曲。神经胶质瘤发生是一个多步骤的过程，涉及遗传和表观遗传的改变。下一代测序的最新应用表明，许多染色质调控相关基因，包括 ATRX、ARID1A、SMARCA4、SMARCA2、SMARCC2、BAF155 和 hSNF5，在神经胶质瘤中发生突变。在这篇综述中，我们总结了影响选定组蛋白修饰酶和染色质修饰物在神经胶质瘤中表达或功能的新发现机制。我们重点介绍涉及 ATRX、组蛋白甲基转移酶 G9a、组蛋白乙酰基转移酶/去乙酰化酶和染色质重塑复合物 SMARCA2/4 的致病机制的选定示例。我们讨论了选定的表观遗传改变对神经胶质瘤病理生物学、信号转导和治疗反应的影响。我们评估了用新型抑制剂靶向缺陷途径的尝试。
