The role of maternal care in shaping CNS function

Maternal care involves the consistent and coordinated expression of a variety of behaviours over an extended period of time, and adverse changes in maternal care can have profound impacts on the CNS and behaviour of offspring. This complex behavioural pattern depends on a number of integrated neuroendocrine mechanisms. This review will discuss the use of animal models in the study of the role of maternal care in shaping CNS function, the contributions of corticosteroid releasing hormone, vasopressin, oxytocin, and prolactin in this process, the molecular mechanisms involved, and the translational relevance of this research.     

Epigenetic Role of Histone 3 Lysine Methyltransferase and Demethylase in Regulating Apoptosis Predicting the Recurrence of Atypical Meningioma

Alteration of apoptosis is related with progression and recurrence of atypical meningiomas (AMs). However, no comprehensive study has been conducted regarding histone modification regulating apoptosis in AMs. This study aimed to determine the prognostic values of certain apoptosis-associated factors, and examine the role of histone modification on apoptosis in AMs. The medical records of 67 patients with AMs, as diagnosed during recent 13 yr, were reviewed retrospectively. Immunohistochemical staining was performed on archived paraffin-embedded tissues for pro-apoptotic factors (CASP3, IGFBP, TRAIL-R1, BAX, and XAF1), anti-apoptotic factors (survivin, ERK, RAF1, MDM2, and BCL2), and the histone modifying enzymes (MLL2, RIZ, EZH1, NSD2, KDM5c, JMJD2a, UTX, and JMJD5). Twenty-six (38.8%) patients recurred during the follow-up period (mean duration 47.7 months). In terms of time-to-recurrence (TTR), overexpression of CASP3, TRAIL-R1, and BAX had a longer TTR than low expression, and overexpression of survivin, MDM2, and BCL2 had a shorter TTR than low expression (P<0.05). Additionally, overexpression of MLL2, UTX, and JMJ5 had shorter TTRs than low expression, and overexpression of KDM5c had a longer TTR than low expression. However, in the multi-variate analysis of predicting factors for recurrence, low expression of CASP3 (P<0.001), and BAX (P<0.001), and overexpression of survivin (P=0.007), and MDM2 (P=0.037) were associated with recurrence independently, but any enzymes modifying histone were not associated with recurrence. Conclusively, this study suggests certain apoptosis-associated factors should be associated with recurrence of AMs, which may be regulated epigenetically by histone modifying enzymes.

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DNA methylation changes in the placenta are associated with fetal manganese exposure

Adequate micronutrient intake, including manganese (Mn), is important for fetal development. Both Mn deficiencies and excess exposures are associated with later-life disease, and Mn accumulates in the placenta. Placental functional alterations may alter fetal programming and lifelong health, and we hypothesized that prenatal exposures to Mn may alter placental function through epigenetic mechanisms. Using Illumina's HumanMethylation450 BeadArray, DNA methylation of >485,000 CpG loci genome-wide was interrogated in 61 placental samples and Mn associations assessed genome-wide via omnibus test (p = 0.045). 713 loci were associated with Mn exposure (p < 0.0001). Five significantly differentially-methylated (p < 1.3 × 10⁻⁷) loci reside in neurodevelopmental, fetal growth and cancer-related genes. cg22284422, within the uncharacterized LOC284276 gene, was associated with birth weight; for every 10% increase in methylation, lower birth weights were observed, with an average decrease of 293.44 g. Our observations suggest a link between prenatal micronutrient levels, placental epigenetic status and birth weight, although these preliminary results require validation.     

Pro-inflammatory and (Epi-)genetic markers in saliva for disease risk in childhood obesity

Background and aimChildhood obesity is an emerging problem often leading to earlier onset of non-communicable diseases in later life. Biomarkers to identify individual risk scores are insufficient in routine clinical practice, which is related to the need for easily sampled, non-invasive survey methods in children. We aimed to investigate and strengthen possible pro-inflammatory markers and epigenetic risk factors in saliva of obese children compared to lean controls.Methods and results19 overweight/obese (OC, 10.1 ± 1.9 years, BMI 27.7 ± 3.2 kg/m²) and 19 lean control children (CC, 9.7 ± 2.5 years, BMI 16.4 ± 1.8 kg/m²) participated in this explorative pilot study. Anthropometric measures, saliva and cheek swab samples were taken. Saliva profiles were examined for acute phase proteins (CRP and neopterin) and pro-inflammatory cytokines (IL-17a/IL-1β/IL-6). Cheek swabs were analyzed to investigate DNA methylation differences with subsequent hierarchical cluster and principal component analyses (PCA). Saliva analysis showed significant increased CRP concentrations in OC compared to CC (p < 0.001). There were no significant differences, but high intra-individual values in neopterin, IL-17a, IL-1β and IL-6. An unsupervised PCA of CpG loci with high variance (σ/σ_max > 0.2) clearly separated OC and CC according to their methylation pattern. Furthermore, a supervised approach revealed 7125 significantly differentially methylated loci, whose corresponding genes were significantly enriched for genes playing roles in e.g., cellular signalling, cytoskeleton organization and cell motility.ConclusionsCRP and methylation status determinations in saliva are suitable as non-invasive methods for early detection of risks for non-communicable diseases in children/adolescents and might be a useful supplementary approach in the routine clinical practice/monitoring.     

N6-甲基腺苷甲基化在射血分数保留性心力衰竭中的作用的研究进展

表观遗传学参与心血管疾病进展的过程。近年研究表明,射血分数保留性心力衰竭(HFpEF)患者的多个基因转录本存在N⁶-甲基腺苷(m⁶A)水平的改变。现介绍m⁶A及其调节因子(甲基化酶、去甲基化酶和甲基化阅读蛋白)与HFpEF的关系,说明m⁶A可能通过影响心肌肥厚与纤维化、细胞自噬、炎症与氧化应激、糖脂代谢参与HFpEF的发生和发展,以期为HFpEF的治疗靶点提供新的研究方向。     

水痘-带状疱疹病毒的潜伏与再激活机制研究进展

水痘-带状疱疹病毒(varicella-zoster virus,VZV)原发性感染通常会引起儿童期水痘,之后病毒可潜伏于人类外周神经节中,在数十年后重新激活造成带状疱疹,也与危及生命的脑炎、血管病变和脑膜炎等疾病有关。VZV潜伏和再激活的机制尚未得到很好的解释,原因之一是VZV只感染人类,无法使用大多数动物及动物来源的神经元模型。越来越多的证据表明,VZV潜伏是表观遗传学调控的,可用于信号通路分析和表观遗传调节鉴定的体外模型为探索VZV潜伏与再激活机制提供了帮助。此文综述了VZV的分子生物学和VZV潜伏与再激活机制方面的研究进展,并提出了未来的研究方向。     

Androgen receptor gene and sex-specific Alzheimer's disease

Women are at a 2-fold risk of developing late-onset Alzheimer's disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect.