Epigenetic memory: A macrophage perspective

The molecular basis of cellular memory is a fascinating topic that progressed with great strides during the last few decades. In the case of cells of the immune system, cellular memory likely extends beyond cell fate determination mechanisms, since immunity can tailor its responses to a potentially hostile environment that is a priori variable if not unpredictable. One particularly versatile innate immune system cell type is the macrophage. These phagocytes occur in all organs and tissues as resident cells or as differentiation products of recruited circulating blood monocytes. They come in many flavours determined by the tissue of residence and by external factors such as microbes. Recently, macrophage epigenome profiling has revealed thousands of chromosomal loci that are differentially active in macrophages, revealing chromosome elements that drive macrophage gene expression. The most dynamic epigenomic mark is nucleosomal histone acetylation. This mark is found at gene promoters and enhancers and correlates very well with gene expression changes. A second mark is H3K4me3, which sharply decorates the promoters of most protein coding genes that are (potentially) expressed. H3K4me3 at promoters is surrounded by its precursor H3K4me1. However, most often H3K4me1 occurs without H3K4me3 at enhancers where it appears together with histone acetylation, but can persist long after acetylation decreased. Hence, the biochemical signal H3K4me1 embodies appears to be a key to the plasticity of macrophage gene expression potential.     

表观遗传学:生物医学研究和眼科研究的新时代

表观遗传学研究已成为生物医学领域的研究热点.越来越多的关于人类疾病发生机制的研究表明,疾病的发生不仅受到遗传因素的影响,也受环境因素的影响,因此表观遗传学因素在各种疾病的发生和发展中发挥很大的作用,眼科疾病的发生也与表观遗传因素有关.迄今为止在表观基因组研究上所取得的进展进一步明确了表观遗传因子在生物发育、炎症、衰老、免疫、新生血管形成、肿瘤以及干细胞生物学等许多复杂的病理生理过程中所扮演的角色.眼科医师应该深入研究表观遗传学三大机制的研究进展及其在各类疾病,尤其是眼科疾病中起到的作用,跟踪近年来应用表观遗传学方法和手段在眼病治疗中取得的进展,明确目前表观遗传学研究发展中面临的主要挑战,关注表观遗传学在眼科研究领域的研究前景.     

The contribution of active and passive mechanisms of 5mC and 5hmC removal in human T lymphocytes is differentiation‐ and activation‐dependent

In mammals, the 5’‐methylcytosine (5mC) modification in the genomic DNA contributes to the dynamic control of gene expression. 5mC erasure is required for the activation of developmental programs and occurs either by passive dilution through DNA replication, or by enzymatic oxidation of the methyl mark to 5‐hydroxymethylcytosine (5hmC), which can persist as such or undergo further oxidation and enzymatic removal. The relative contribution of each mechanism to epigenetic control in dynamic biological systems still remains a compelling question. To explore this critical issue, we used primary human T lymphocytes, in which two cellular states can be clearly identified, namely quiescent naïve T cells, which are slowly or rarely proliferating, and rapidly proliferating activated T cells. We found that active mechanisms of methylation removal were selectively at work in naïve T cells, while memory T lymphocytes entirely relied on passive, replication‐dependent dilution, suggesting that proliferative capacity influences the choice of the preferential demethylation mechanism. Active processes of demethylation appear to be critical in quiescent naïve T lymphocytes for the maintenance of regulatory regions poised for rapid responses to physiological stimuli.     

原发性干燥综合征生物标志物的研究进展

目前原发性干燥综合征(pSS)诊断仍然依赖于侵入性小涎腺活检手术,常导致其早期诊断异常艰难,因此筛选特定生物标志物可能对pSS诊断和个体化治疗极为有益。本文回顾传统标志物及与B细胞活化和表观遗传相关的新标志物,并综述组学标志物研究进展。尽管生物标志物前景较好,但其可靠性仍需扩大样本量进行验证。     

表观遗传与肿瘤代谢研究进展

表观遗传学主要关注DNA甲基化、组蛋白修饰、染色质重塑，以及非编码RNA等超越DNA序列的基因调控机制。表观遗传机制参与了个体发育、细胞命运决定和肿瘤发生等众多生物学过程。其中表观遗传信息以各种染色质修饰和高级结构的形式存储于基因组中，它的建立和维持与细胞代谢紧密相关。肿瘤细胞中存在的代谢改变包括有氧糖酵解、葡萄糖摄取量增加、谷氨酰胺代谢异常活跃、利用非主要供能物质供能等，这些改变满足了肿瘤发生发展过程中旺盛的能量和物质需求，帮助细胞适应缺氧的肿瘤微环境，进而为肿瘤增殖、侵袭、迁移等生物活动提供支持。肿瘤细胞的表观遗传修饰与代谢之间存在复杂的相互关系，一方面肿瘤细胞中的代谢产物作为表观修饰酶的辅因子、修饰供体或拮抗分子影响表观修饰景观；另一方面表观遗传修饰可以直接改变代谢酶和转运蛋白的表达或通过影响信号转导和转录因子的表达调控细胞代谢。本文综述了不同表观遗传学过程与肿瘤细胞代谢之间的相互作用，并展望两者在肿瘤治疗中的潜在应用前景。     

表观遗传修饰在神经退行性变性疾病中的作用研究进展

表观遗传修饰对神经发育、神经干细胞命运决定和神经系统的生理功能发挥具有重要的调节作用。异常的表观遗传修饰与阿尔茨海默病、帕金森病和亨廷顿病等神经退行性变性疾病的发生和发展有密切关系：异常升高的DNA甲基化修饰抑制了一些修复基因的表达，影响亨廷顿病进展；阿尔茨海默病患者大脑中H3K27ac和H3K9ac组蛋白修饰增加，影响神经变性；RNA甲基化修饰在阿尔茨海默病和帕金森病两种疾病动物模型中呈现差异化的改变。因此，表观遗传修饰可能作为神经系统疾病的潜在治疗靶点。本文综述了表观遗传修饰参与神经退行性变性疾病及其分子机制的最新研究进展。     

Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.