Anxiety in mice and men: a comparison

Anxiety is one of the most fundamental emotions required to survive or to cope with potential threatening stimuli. Under certain circumstances, it can change to excessive or maladaptive response and might manifest in anxious personality or even anxiety disorders. Genetic studies provide a number of promising candidate genes that, however, account for only a few percent of the phenotypic variance. Social and material environmental effects such as stressful life events, drugs or chemicals and particular behavioural influences such as parental care are suggested to interact with gene effects presumably involving epigenetic processes. Such interaction probably modifies an individual’s predisposition, personality and susceptibility to develop normal or low anxiety or even maladaptive or excessive anxiety. Since human anxiety involves complex emotions as well as cognitions, unique experiences and an individual genetic make-up, studies trying to clarify the complex and functionally interwoven pathogenesis of anxious personality or anxiety disorders often adopt a reductionistic, simplifying approach. Therein, mice constitute an invaluable tool for modelling human anxiety in its various forms as they display remarkable similarities on anatomical, physiological, biochemical, molecular and behavioural levels. This review aims to fit observations and results obtained from men and mice on behavioural, genetic and environmental levels in response to different threatening stimuli elucidating different genetic and epigenetic effects. Dedicated to the special issue on anxiety.     

Histone methylation in pancreatic cancer and its clinical implications

Pancreatic cancer (PC) is an aggressive human cancer. Appropriate methods for the diagnosis and treatment of PC have not been found at the genetic level, thus making epigenetics a promising research path in studies of PC. Histone methylation is one of the most complicated types of epigenetic modifications and has proved crucial in the development of PC. Histone methylation is a reversible process regulated by readers, writers, and erasers. Some writers and erasers can be recognized as potential biomarkers and candidate therapeutic targets in PC because of their unusual expression in PC cells compared with normal pancreatic cells. Based on the impact that writers have on the development of PC, some inhibitors of writers have been developed. However, few inhibitors of erasers have been developed and put to clinical use. Meanwhile, there is not enough research on the reader domains. Therefore, the study of erasers and readers is still a promising area. This review focuses on the regulatory mechanism of histone methylation, and the diagnosis and chemotherapy of PC based on it. The future of epigenetic modification in PC research is also discussed.     

Role of epigenetics in transformation of inflammation into colorectal cancer

Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer(CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.     

The biological basis of sexual orientation: How hormonal,genetic, and environmental factors influence to whom we are sexually attracted

Humans develop relatively stable attractions to sexual partners during maturation and present a spectrum of sexual orientation from homosexuality to heterosexuality encompassing varying degrees of bisexuality, with some individuals also displaying asexuality. Sexual orientation represents a basic life phenomenon for humans. However, the molecular mechanisms underlying these diverse traits of sexual orientation remain highly controversial. In this review, we systematically discuss recent advancements in sexual orientation research, including those related to measurements and associated brain regions. Current findings regarding sexual orientation modulation by hormonal, genetic, maternal immune system, and environmental factors are summarized in both human and model systems. We also emphasize that future studies should recognize the differences between males and females and pay more attention to minor traits and the epigenetic regulation of sexual orientation. A comprehensive view of sexual orientation may promote our understanding of the biological basis of sex, and that of human reproduction, and evolution.     

表观遗传学与视网膜疾病的关联研究

表观遗传学是指在DNA序列无变化的情况下,基因表达状态发生可遗传的改变的情况,是目前基因组测序后人类基因组的重大研究方向之一。表观遗传学的本质是表观遗传修饰,其对基因表达与功能的调节方式主要包括DNA甲基化、组蛋白乙酰化及非编码RNA,如小RNA（miRNA）。研究认为,表观遗传学在多种视网膜疾病的发病过程中发挥重要作用,许多动物实验研究均表明,表观遗传学可能与视网膜纤维化、视网膜色素变性（RP）、年龄相关性黄斑变性（AMD）、糖尿病视网膜病变（DR）等视网膜疾病的发病均有重要关联。通过对表观遗传学认识的加深和理解,一些与表观遗传学相关的药物正在临床试验中,有望用于视网障疾病的治疗．     

BRCA1 promoter methylation is associated with increased mortality among women with breast cancer

Promoter-CpG island hypermethylation has been proposed as an alternative mechanism to inactivate BRCA1 in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer etiology and progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. Promoter methylation of BRCA1 was assessed in 851 archived tumor tissues collected from a population-based study of women diagnosed with invasive or in situ breast cancer in 1996–1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in invasive cancers (P = 0.02) and among premenopausal cases (P = 0.05). BRCA1 promoter methylation was associated with increased risk of breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05–2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02–2.18). Neither dietary methyl intakes in the year prior to the baseline interview nor the functional polymorphisms in one-carbon metabolism were associated with BRCA1 methylation status. Our study is the first epidemiological investigation on the prognostic value of BRCA1 promoter methylation in a large population-based cohort of breast cancer patients. Our results indicate that BRCA1 promoter methylation is an important factor to consider in predicting breast cancer survival. This work was supported by grants from the National Institutes of Health (CA109753 to JC; DK55865 to SZ) and in part by grants from Department of Defense (BC031746), National Cancer Institute and the National Institutes of Environmental Health and Sciences (UO1CA/ES66572, UO1CA66572, P30CA013696, P30ES09089 and P30ES10126); and by the University of North Carolina Clinical Nutrition Research Unit (DK56350) and Center for Environmental Health and Susceptibility (ES10126). Xu, X. is a recipient of the Predoctoral Traineeship Award (W81XWH-06-1-0298) of Department of Defense Breast Cancer Research Program.     

DNA甲基化对男性精液质量影响的研究进展

DNA甲基化是表观遗传学修饰的主要形式之一,对个体发育具有至关重要的作用.近年来,大量研究表明不育男性的精子中存在不同基因异常甲基化.本文主要阐述了印记基因(H19、FAM50B、GNAS、MEST、KCNQ1OT1、SNRPN)和其他相关基因(P16、LINE-1、MTHFR、SLC9B1、DDR1)异常甲基化会对精液质量(包括精子数目、活力和形态)产生不同程度的影响,从而导致男性不育.因此,检测精子特定基因的DNA甲基化程度有可能成为针对男性不育的新型辅助诊断手段.