早期负性经历的表观遗传学研究进展

表观遗传学（epigenetics）是指不涉及DNA序列改变、可以通过有丝分裂和减数分裂进行遗传的基因表达变化的遗传学分支领域。目前研究主要集中在DNA甲基化、组蛋白密码、染色质重塑和非编码RNA调控等方面。早期负性经历是指个体出生早年所经历的不良生活事件,还包括个体出生前所经历的负性生活事件。大量研究表明早期负性经历对个体成年后的行为会造成明显影响。本文将综述早期负性经历中表观遗传的各种机制。     

胚胎发育的精细表观遗传调控

正表观遗传学的概念起源于对进化和发育的研究,早期的表观遗传学涵盖了个体从受精卵到发育成熟过程中的所有事件.而随着对遗传物质的鉴定和DNA双螺旋结构的解析,分子生物学日益成熟起来,科学家们逐渐清楚地意识到,成熟个体的细胞中含有的基因是相同的,但却产生了各种不同的细胞表型.这种基因表达的空间和时间差异性使得科学家们更加明确地进行基因表达调控的研究,从而形成了现代表观遗传学的概念,即不改变DNA序列的可遗传性改变.     

孕期营养不良影响子代生长发育的表观遗传机制

表观遗传学是一门研究核酸序列不变,基因的可遗传变化的表达和调控的遗传学分支学科,主要包括DNA甲基化、组蛋白共价修饰、染色质重塑、基因沉默和RNA调控等机制。近年来,表观遗传修饰的检测方法也逐渐完善。营养物质不仅构成生命体的物质基础,还可以通过表观遗传调控机制对生命体的代谢活动进行一定的调节。由于早期胚胎和哺乳期幼仔产后早期所需营养物质全部和部分来源于母体孕期营养,因此本文综述了母体孕期营养水平对后代生长发育的表观遗传调节机制——DNA甲基化和组蛋白修饰。     

表观遗传修饰在抑郁症发生发展中的作用

表观遗传学指的是DNA序列不发生改变而产生长时程可遗传基因功能变化的生物学现象,其主要内容包括组蛋白修饰、DNA甲基化和miRNA调控等。很多研究表明表观遗传学修饰与抑郁症的发生发展有关,表观遗传学修饰的失调是阐明抑郁症发病机制的关键。目前,表观遗传修饰已成为抑郁症发病机制研究的一个新的方向。本文对近几年抑郁症表观遗传学发病机制的研究进展进行综述,以期为抑郁症的发病机制的研究和治疗提供参考。     

表观遗传学与肺癌

表观遗传是在指不影响遗传序列的情况下影响型状表达的方法。除了经典遗传方面,如点突变、颠换、插入与肺癌的发生有关,近年来研究显示表观遗传学对肺癌的发生也起到了重要的作用。本文主要从表观遗传学角度,简述了DNA甲基化、组蛋白修饰、非编码RNA尤其是mi RNA与肺癌的关系,甲基化主要是通过抑制原癌基因,促进抑癌基因表达导致肺癌,组蛋白修饰会促进抑癌基因的表达,非编码RNA可以作为肺癌诊断的生物标记物,为肺癌的早期诊断提供依据。     

植物DNA甲基化及其表观遗传作用

表观遗传学(epigenetics)是研究没有DNA序列变化的、可遗传的基因表达的改变。目前研究表明,表观遗传学在植物生长发育过程中起着极其重要的作用,主要通过包括DNA甲基化、RNA干涉、基因组印记、转基因沉默等多个方面来调控植物的生长发育。其中,DNA甲基化是表观遗传学的最重要研究内容之一,是调节基因组功能的重要手段。现对植物DNA甲基化的特征、维持机制、调控机制、表观遗传作用及其研究方法进行简要论述。     

表观遗传学及其与疾病相关性

表观遗传学(Epigenetics)是指基因的DNA序列不发生改变的情况下,基因的表达水平与功能发生改变,并产生可遗传表型的遗传现象。主要内容包括DNA甲基化,组蛋白共价修饰,染色质重塑,非编码RNA 4个调控机制。这些表观遗传学变化与多种疾病的发生发展有关,该文就表观遗传学及其与疾病相关性作一综述。     

前列腺癌的DNA甲基化及其临床应用

目前认为恶性肿瘤的形成是遗传和表观遗传机制共同作用的结果。表观遗传机制包括DNA甲基化、组蛋白修饰和miRNA。DNA异常甲基化(高甲基化和低甲基化)是前列腺癌最具特征的表观遗传改变, 它能够导致基因组不稳定, 调控基因的异常表达, 在前列腺癌的形成和发展中起到重要作用。同时, DNA甲基化作为前列腺癌表观遗传研究的一个热点, 为临床前列腺癌的早期诊断、预后评估及药物治疗提供新的方法和途径。文章根据前列腺癌的DNA高甲基化和低甲基化的最新研究成果阐述了前列腺癌形成的表观遗传学机制, 并且讨论了它们在前列腺癌临床转化方面的最新研究进展。     

表观遗传学研究进展

表观遗传学是在基因组DNA序列不发生变化的条件下,基因表达发生的改变也是可以遗传的,导致可遗传的表现型变化。表观遗传学主要包括DNA甲基化作用、组蛋白修饰作用、染色质重塑、遗传印记、随机染色体(X)失活及RNA世界等。与表观遗传学相关的疾病主要有肿瘤、心血管病、精神病和自身免疫系统性病等。现就表观遗传学与疾病进行综述。     

表观遗传学——理论·方法·研究进展(1)

现代生物（包括人类在内）从祖先基因组中所获得的生长、发育和进化信息并不仅仅是基因序列。在DNA序列不发生变化的条件下,基因表达发生的改变也可以是遗传的,导致表观遗传变异。表观遗传学就指研究不涉及遗传物质核苷酸序列的改变、但可以通过有丝分裂和减数分裂实现代间传递（遗传）的生物现象的遗传学分支领域、从根本上讲,表观遗传是环境因素和细胞内的遗传物质之间发生交互作用的结果,目前表观遗传学研究主要集中在甲基化、小RNA和染色质重塑等方面。副突变、亲代印记、性别相关性基因剂量补偿效应和转基因沉默等是典型的表观遗传现象,相关研究有利于揭示生长发育、杂种优势、作物抗逆和人类疾病等许多生命现象的本质。     

Genetic epidemiology, genetic maps and positional cloning

Genetic epidemiology developed in the middle of the last century, focused on inherited causes of disease but with methods and results applicable to other traits and even forensics. Early success with linkage led to the localization of genes contributing to disease, and ultimately to the Human Genome Project. The discovery of millions of DNA markers has encouraged more efficient positional cloning by linkage disequilibrium (LD), using LD maps and haplotypes in ways that are rapidly evolving. This has led to large international programmes, some promising and others alarming, with laws about DNA patenting and ethical guidelines for responsible research still struggling to be born.     

Early life stress and telomere length: Investigating the connection and possible mechanisms

How can adverse experiences in early life, such as maltreatment, exert such powerful negative effects on health decades later? The answer may lie in changes to DNA. New research suggests that exposure to stress can accelerate the erosion of DNA segments called telomeres. Shorter telomere length correlates with chronological age and also disease morbidity and mortality. Thus, telomere erosion is a potential mechanism linking childhood stress to health problems later in life. However, an array of mechanistic, methodological, and basic biological questions must be addressed in order to translate telomere discoveries into clinical applications for monitoring health and predicting disease risk. This paper covers the current state of the science and lays out new research directions.     

Cumulative lifetime maternal stress and epigenome-wide placental DNA methylation in the PRISM cohort

Evolving evidence links maternal stress exposure to changes in placental DNA methylation of specific genes regulating placental function that may have implications for the programming of a host of chronic disorders. Few studies have implemented an epigenome-wide approach. Using the Infinium HumanMethylation450 BeadChip (450K), we investigated epigenome-wide placental DNA methylation in relation to maternal experiences of traumatic and non-traumatic stressors over her lifetime assessed using the Life Stressor Checklist-Revised (LSC-R) survey (n = 207). We found differential DNA methylation at epigenome-wide statistical significance (FDR = 0.05) for 112 CpGs. Additionally, we observed three clusters that exhibited differential methylation in response to high maternal lifetime stress. Enrichment analyses, conducted at an FDR = 0.20, revealed lysine degradation to be the most significant pathway associated with maternal lifetimes stress exposure. Targeted enrichment analyses of the three largest clusters of probes, identified using the gap statistic, were enriched for genes associated with endocytosis (i.e., SMAP1, ANKFY1), tight junctions (i.e., EPB41L4B), and metabolic pathways (i.e., INPP5E, EEF1B2). These pathways, also identified in the top 10 KEGG pathways associated with maternal lifetime stress exposure, play important roles in multiple physiological functions necessary for proper fetal development. Further, two genes were identified to exhibit multiple probes associated with maternal lifetime stress (i.e., ANKFY1, TM6SF1). The methylation status of the probes belonging to each cluster and/or genes exhibiting multiple hits, may play a role in the pathogenesis of adverse health outcomes in children born to mothers with increased lifetime stress exposure.     

The polyamine inhibitor alpha-difluoromethylornithine modulates hippocampus-dependent function after single and combined injuries

Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury.     

Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

DNA methylation of IGF2, GNASAS,INSIGF and LEP and being born small for gestational age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (<32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; “AGA”). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10^-13) and head circumference at birth (P=4.1x10^-13). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.     

Influence of altitude (3,515 m) birth on the reproductive organs of male rats

Adult male rats were exposed to a simulated altitude of 3,515 m continuously for a period of 7, 14 and 21 days. There were atrophic changes in testis, epididymis and vas deferens, fall in levels of GPC and sialic acid and increase in alkaline and acid phosphatase activity of these organs. Sperm quality deteriorated. The adverse effects of hypoxia were more pronounced if the exposure was extended to 14 days, but on further increasing the duration of exposure to 21 days, there was a tendency to recover. Male rats born at high altitude (3,515 m), i.e. F₂, F₃ and F₄ generations were used and compared with rats born at sea level. The animals born at HA showed a deterioration of seminal quality, the tests showed lesions, epididymal and vasal physiology were affected. The adverse effects of high altitude were more prominent in F₂ generations, while F₃ and F₄ generations showed adaptation to high altitude.     

Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation

The association between an adverse early life environment and increased susceptibility to later-life metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease is described by the developmental origins of health and disease hypothesis. Employing a rat model of maternal high fat (MHF) nutrition, we recently reported that offspring born to MHF mothers are small at birth and develop a postnatal phenotype that closely resembles that of the human metabolic syndrome. Livers of offspring born to MHF mothers also display a fatty phenotype reflecting hepatic steatosis and characteristics of non-alcoholic fatty liver disease. In the present study we hypothesised that a MHF diet leads to altered regulation of liver development in offspring; a derangement that may be detectable during early postnatal life. Livers were collected at postnatal days 2 (P2) and 27 (P27) from male offspring of control and MHF mothers (n = 8 per group). Cell cycle dynamics, measured by flow cytometry, revealed significant G0/G1 arrest in the livers of P2 offspring born to MHF mothers, associated with an increased expression of the hepatic cell cycle inhibitor Cdkn1a. In P2 livers, Cdkn1a was hypomethylated at specific CpG dinucleotides and first exon in offspring of MHF mothers and was shown to correlate with a demonstrable increase in mRNA expression levels. These modifications at P2 preceded observable reductions in liver weight and liver∶brain weight ratio at P27, but there were no persistent changes in cell cycle dynamics or DNA methylation in MHF offspring at this time. Since Cdkn1a up-regulation has been associated with hepatocyte growth in pathologic states, our data may be suggestive of early hepatic dysfunction in neonates born to high fat fed mothers. It is likely that these offspring are predisposed to long-term hepatic dysfunction.     

The association between adverse childhood experiences and epigenetic age acceleration in the Canadian longitudinal study on aging (CLSA)

Research examining the association between exposure to a wide range of adverse childhood experiences (ACEs) and accelerated biological aging in older adults is limited. The purpose of this study was to examine the association of ACEs, both as a cumulative score and individual forms of adversity, with epigenetic age acceleration assessed using the DNA methylation (DNAm) GrimAge and DNAm PhenoAge epigenetic clocks in middle and older-aged adults. This cross-sectional study analyzed baseline and first follow-up data on 1445 participants aged 45–85 years from the Canadian Longitudinal Study on Aging (CLSA) who provided blood samples for DNAm analysis. ACEs were assessed using a validated self-reported questionnaire. Epigenetic age acceleration was estimated by regressing each epigenetic clock estimate on chronological age. Cumulative ACEs score was associated with higher DNAm GrimAge acceleration (β: 0.07; 95% CI: 0.02, 0.11) after adjusting for covariates. Childhood exposure to parental separation or divorce (β: 0.06; 95% CI: 0.00, 0.11) and emotional abuse (β: 0.06; 95% CI: 0.00, 0.12) were associated with higher DNAm GrimAge acceleration after adjusting for other adversities and covariates. There was no statistical association between ACEs and DNAm PhenoAge acceleration. Early life adversity may become biologically embedded and lead to premature biological aging, in relation to DNAm GrimAge, which estimates risk of mortality. Strategies that increase awareness of ACEs and promote healthy child development are needed to prevent ACEs.