长链非编码RNA与表观遗传调控

近年来,表观遗传学(epigenetics)备受关注.表观遗传调控的方式主要包括DNA甲基化、组蛋白修饰和染色质重塑等.ENCODE计划及随后的研究发现,人类基因组中仅有很小一部分DNA序列负责编码蛋白质,而其余大部分被转录为非编码RNA(non-codingRNA,ncRNA).其中长链非编码RNA(long non-codingRNA,lncRNA)是一类长度大于200nt并且缺乏蛋白质编码能力的RNA分子.越来越多的研究表明,lncRNAs能够通过表观遗传调控、转录调控以及转录后调控等多个层面调节基因的表达,从而参与细胞增殖、分化和凋亡等多种生物学过程.本文将着重综述lncRNAs在表观遗传调控中的作用及其最新的研究进展.     

甲基苯丙胺成瘾的表观遗传学机制

苯丙胺类兴奋剂是全世界第二大滥用程度的药物,甲基苯丙胺作为苯胺类兴奋剂中的主要药物,是中国滥用的“头号毒品”。而现有的研究对甲基苯丙胺成瘾机制尚不清晰,且临床上对药物成瘾的治疗依然存在无药可医的局面。因此,发现新的成瘾机制和治疗策略尤为迫切。甲基苯丙胺成瘾与额前叶皮质（mPFC）、中脑腹侧被盖区（VTA）和伏隔核（NAc）中的多巴胺（DA）、谷氨酸（Glu）、去甲肾上腺素（NE）和血清素（SNRIS）等神经递质的异常释放有关。研究表明,这些神经递质受到表观遗传机制中组蛋白乙酰化、甲基化、泛素化和非编码RNA等调节,某些基因的表达在甲基苯丙胺的诱导过程中增强或被抑制,导致甲基苯丙胺依赖性产生。本文将针对表观遗传学对甲基苯丙胺成瘾机制的影响进行着重论述,以期推进临床开发甲基苯丙胺戒断药物的研究。     

Editor's choice: Large,Male Germ Cell-Specific Hypomethylated DNA Domains With Unique Genomic and Epigenomic Features on the Mouse X Chromosome

To understand the epigenetic regulation required for germ cell-specific gene expression in the mouse, we analysed DNA methylation profiles of developing germ cells using a microarray-based assay adapted for a small number of cells. The analysis revealed differentially methylated sites between cell types tested. Here, we focused on a group of genomic sequences hypomethylated specifically in germline cells as candidate regions involved in the epigenetic regulation of germline gene expression. These hypomethylated sequences tend to be clustered, forming large (10 kb to ∼9 Mb) genomic domains, particularly on the X chromosome of male germ cells. Most of these regions, designated here as large hypomethylated domains (LoDs), correspond to segmentally duplicated regions that contain gene families showing germ cell- or testis-specific expression, including cancer testis antigen genes. We found an inverse correlation between DNA methylation level and expression of genes in these domains. Most LoDs appear to be enriched with H3 lysine 9 dimethylation, usually regarded as a repressive histone modification, although some LoD genes can be expressed in male germ cells. It thus appears that such a unique epigenomic state associated with the LoDs may constitute a basis for the specific expression of genes contained in these genomic domains.     

Epigenetic mechanisms regulating fate specification of neural stem cells

Neural stem cells (NSCs) possess the ability to self-renew and to differentiate along neuronal and glial lineages. These processes are defined by the dynamic interplay between extracellular cues including cytokine signalling and intracellular programmes such as epigenetic modification. There is increasing evidence that epigenetic mechanisms involving, for example, changes in DNA methylation, histone modification and non-coding RNA expression are closely associated with fate specification of NSCs. These epigenetic alterations could provide coordinated systems for regulating gene expression at each step of neural cell differentiation. Here we review the roles of epigenetics in neural fate specification in the mammalian central nervous system.     

上皮细胞转分化及其表观遗传学调控

上皮细胞转分化现象及其与疾病发生发展的关系,近年已成为细胞生物学、免疫学等多学科关注的聚焦点。转分化作为细胞分化发育的基本生物学现象,存在于机体诸多生理病理过程,也受表观遗传学的调控。相对于经典遗传学而言,表观遗传学作为一门新兴学科,其为生物体的基因表达调控及遗传现象提供了新的理论阐释。现知,DNA甲基化、组蛋白修饰及非编码RNA等均可导致上皮细胞基因发生表观遗传改变,与上皮细胞转分化的发生发展密切相关,并在该过程中发挥重要的调控作用。进一步阐明细胞转分化的分子基础及其表观遗传学调控机制,将有助于认识生命现象基本过程,并可为炎症性疾病、自身免疫病、器官纤维化,以及肿瘤发生与转移等机制的研究与防治,提供新的思路和应对策略。对上皮细胞转分化与表观遗传学调控关系作一简述。     

组蛋白甲基化研究进展

组蛋白甲基化是表观遗传修饰方式中的一种,参与异染色质形成、基因印记、X染色体失活和基因转录调控.组蛋白甲基化过程的异常参与多种肿瘤的发生.既往认为组蛋白甲基化是稳定的表观遗传标记,而组蛋白去甲基化酶的发现对这一观点提出了挑战,也为进一步深入研究组蛋白修饰提供新的途径.     

Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich''s ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.