骨质疏松症与表观遗传学

骨质疏松症是老年人常见的退行性疾病,老龄化的社会结构也使得骨质疏松症具有广泛的发病人群,其继发骨折的风险较高,危害性大。骨质疏松症以骨强度下降,骨折风险增加为特征的一种全身性骨骼系统疾病,它受年龄、性别、体内性激素水平、遗传、环境等多方面因素的影响。近年来,随着基因技术的发展,遗传因素与骨质疏松症的相关研究也逐渐增加,其热点之一为表观遗传学。表观遗传是不同于传统孟德尔遗传定律,不通过改变DNA序列所致的可遗传的基因表达变化,它包括DNA甲基化、组蛋白修饰、微小RNA(miRNA)、染色质重塑等。本文就骨质疏松症与表观遗传学的研究现状进行阐述,旨在揭示骨质疏松症在表观遗传学方面可能的发病机制。     

肝细胞癌的表观遗传学研究进展

肝细胞癌简称肝癌(hepatocellular carcinoma)的发病率、病死率呈逐年上升趋势,尽管几种主要危险致病因素已经比较明确,但是肝癌发生的确切的分子生物学机制尚不完全清楚.近年来越来越多的证据表明,表观遗传修饰(epigenetics)在肝癌的发生发展中具有非常重要的作用.本文将就DNA的异常甲基化、组蛋白异常修饰与肝癌的关系,肝癌的表观遗传学检测及表观遗传学治疗现状做一综述.     

表观遗传学在骨性关节炎研究中的进展

骨性关节炎(osteoarthritis,OA)是一种最常见的以关节软骨退变为主要病理改变的年龄相关性退化疾病,可表现为不同程度的关节软骨丢失、骨质增生、软骨下骨改变和滑膜炎等.近年来越来越多的证据表明表观遗传修饰在OA发生发展中扮演着非常重要的作用.表观遗传学研究与DNA序列无关的基因表达调控,包括DNA甲基化、组蛋白修饰、miRNA、基因印记等.表观遗传调控可以作为研究OA发病机制的一个新思路.本文就表观遗传学与OA的相关性做一综述.     

表观遗传学与肝癌关系的研究进展

肝细胞肝癌（Hepatocellular carcinoma,HCC）简称肝癌,是人类最常见的恶性肿瘤之一.我国是肝癌的高发区,发病人数居首位,死亡率在各种恶性肿瘤中占据第二位.它是一种容易侵袭转移的恶性肿瘤,临床就诊者多属中晚期病人,手术切除率低.未经治疗的肝癌患者5年生存率极低,大约0～14％[1],即使早期切除,术后5年复发率也在60％以上,小肝癌仍达40％ ～ 50％[2].其主要发病原因是肝炎病毒（HBV、HCV）感染,黄曲霉毒素、过量酒精摄入及遗传性肝硬化也可导致肝癌发生,但发病机制尚不清楚.过去认为环境因素作用导致遗传学改变是肿瘤发生的主要原因,但大量的研究表明,在肝癌发生过程中,只有少数癌基因或抑癌基因发生突变.近年来,表观遗传学（Epigenetics）的兴起为解答这些问题提供了新思路.本文就DNA甲基化、组蛋白修饰和miRNA调控与肝癌关系的研究进展作一综述.     

表观遗传学与乳腺癌

表观遗传学是基于非DNA序列改变而产生的基因表达的变化,与肿瘤的发生密切相关,具有可逆性和遗传性,主要包括DNA甲基化、组蛋白修饰和染色体重组,它们相互作用,影响基因表达.乳腺癌中,表观遗传调节改变了一些重要基因的表达,导致了肿瘤的产生和发展.表观遗传学的研究对乳腺癌的发生、发展、早期诊断、预后评估、治疗和复发监测产生了深远的影响.     

表观遗传学与乳腺癌

表观遗传学是基于非DNA序列改变而产生的基因表达的变化,与肿瘤的发生密切相关,具有可逆性和遗传性,主要包括DNA甲基化、组蛋白修饰和染色体重组,它们相互作用,影响基因表达。乳腺癌中,表观遗传调节改变了一些重要基因的表达,导致了肿瘤的产生和发展。表观遗传学的研究对乳腺癌的发生、发展、早期诊断、预后评估、治疗和复发监测产生了深远的影响。     

绝经后骨质疏松症发病机制的表观遗传学研究进展

表观遗传学修饰是指在DNA序列未变化情况下发生可遗传的基因表达的变化,主要机制包括DNA甲基化、组蛋白修饰、非编码RNAs、染色质修饰等。绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)属于原发性骨质疏松症的一种,主要是由于绝经后女性激素水平改变等原因致使骨代谢失衡,骨微结构破坏,骨量减少。近年来,大量研究证实了表观遗传学参与绝经后骨质疏松症的发生发展,本文将从DNA甲基化、组蛋白修饰和非编码RNAs这三个方面综述绝经后骨质疏松症在表观遗传学方面的发病机制。     

表观遗传学与糖尿病肾脏病

糖尿病肾脏病(diabetic kidney disease,DKD)是糖尿病患者普遍存在的一种微血管并发症,它也是糖尿病患者死亡的主要病因之一。近年来大量体内和体外实验发现和证实,表观遗传学通过多种机制改变基因表达,造成细胞功能异常,最终导致DKD的发生与进展。本文从DNA甲基化、组蛋白修饰和非编码核糖核酸(ncRNA)参与DKD肾小球足细胞损伤、肾小管上皮细胞损伤和炎性反应等病理生理过程的研究进展做一综述。     

精子发生过程中的表观遗传学调控

精子发生是由精原细胞增殖、精母细胞减数分裂以及精子形成所组成的连续过程。精子发生也是染色质不断凝集的过程,最终在精子头部达到高度浓缩状态。近年来的研究表明,表观遗传调控在精子发生过程中发挥作用。我们将从三方面简要阐述精子发生过程中的表观遗传学调控机制:DNA甲基化,组蛋白修饰以及非编码RNA。这些表观因素之间也可以互相调控,通过调控基因表达、转座子活化、性染色体失活以及基因印记等,在精子发生,受精以及胚胎发育过程中扮演重要角色。     

肥胖导致男性不育的表观遗传机制研究进展

肥胖引发表观遗传改变可导致男性出现不育表型。关于肥胖与男性不育的关系问题,早期研究多集中于内分泌方面。近年研究发现肥胖还可以引发机体表观遗传改变,如DNA甲基化,残余组蛋白修饰,小RNA等,影响精子成熟发育。DNA甲基化是胞嘧啶-磷酸-鸟嘌呤二核苷酸的胞嘧啶残基上的调节标记,肥胖导致DNA甲基化异常,并改变mRNA表达丰度,还可以影响印记基因表达出现印记基因病。残余组蛋白修饰方式包括甲基化、乙酰化等,它们可以相互作用或协同作用,以保证精子正常生长发育。肥胖可以改变甲基化酶及乙酰化酶活性,直接影响残余组蛋白的甲基化和乙酰化;还可以影响精子小RNA的表达,导致精子缺陷。本文就肥胖引起的表观遗传学改变及导致男性不育的作用机制做逐一综述。     

A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate

BACKGROUND: Folate and methyl-group deficiency has been linked to prostate cancer susceptibility, yet the mechanisms underlying these observations are incompletely understood. The region of the genome containing the imprinted genes insulin-like growth factor 2 (Igf2) and H19, both of which display oncogenic functions, may be particularly sensitive to environmental influences. METHODS: To determine whether a methyl-deficient diet impacts epigenetic controls at the Igf2-H19 locus, we placed C57BL/6 mice containing a polymorphism at the imprinted Igf2-H19 locus on a choline and methionine deficient (CMD) diet. We interrogated this locus for expression and epigenetic changes in prostate tissues. RESULTS: A significant increase in both Igf2 and H19 expression was found in CMD prostate tissues compared to controls. These expression changes were reversible with shorter exposure to the CMD diet. Chromatin immunoprecipitation (ChIP) revealed significant decreases in repressive histone modifications (dimethyl-H3K9) within the H19 promoter, as well as Igf2 P2 and P3 promoters. DNA methylation within these promoters was not altered. No significant change in Igf2 or H19 imprinting was observed. CONCLUSIONS: These findings highlight the plasticity of the epigenome in an epithelial organ vulnerable to neoplastic change. They further suggest that chromatin modifications are more susceptible to methyl-deficient diets than DNA methylation at this locus.     

Epigenetics in prostate cancer: biologic and clinical relevance

Context

Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence.

Objective

To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge.

Evidence acquisition

PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications.

Evidence synthesis

Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance.

Conclusions

Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic.