维生素D缺乏与儿童疾病表观遗传学研究

维生素D不仅对骨代谢有着经典的作用,同时在免疫、细胞增殖和分化中有重要的作用。最近的研究发现,孕期维生素D水平也可能通过表观遗传修饰影响到后代儿童期非骨骼系统疾病的易感性,如哮喘,自身免疫性疾病和神经精神疾病等。本文将综述维生素D缺乏与儿童疾病表观遗传学的研究进展。     

DNA甲基化在肝脏再生中的研究现状与展望

目的总结目前DNA甲基化与肝脏再生关系的研究现状。方法检索国内外相关文献,对肝细胞甲基化水平、基因表达调控、甲基化相关蛋白与肝脏再生关系的研究进行综述。结果 DNA甲基化作为生物体内一种重要的表观遗传调控方式,近年来在肝脏再生中的作用越来越被重视。现有的研究已经发现,在肝脏再生过程中存在基因组低甲基化、相关增殖基因甲基化改变以及DNA甲基化转移酶、含植物同源结构域和环指结构域泛素样蛋白1调控肝脏再生等表观遗传现象。结论 DNA甲基化与肝脏再生之间存在着诸多的联系,从DNA甲基化水平调节肝脏再生有望在不久的将来成为现实。     

圆锥角膜病因学研究进展——遗传、环境刺激、表观遗传的相互作用

圆锥角膜是一种扩张性角膜疾病,以角膜中央变薄、向前凸出呈锥状为特征,可严重影响视力。圆锥角膜病因复杂,迄今为止尚未完全明确,可能是遗传、表观遗传和环境刺激之间相互作用的结果。本文旨在对近年来圆锥角膜病因学的研究进展进行综述,并对未来该领域的研究方向进行展望:阐明表观遗传学的调控路径可能是明确病因的关键;3D培养的体外模型可望为探索圆锥角膜病因和推进治疗提供依据。     

Resveratrol Based Oral Nutritional Supplement Produces Long-Term Beneficial Effects on Structure and Visual Function in Human Patients

Background: Longevinex^® (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D₃ and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy. Methods: We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus). Results: We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient’s pathophysiology. No side effects were observed. Conclusions: These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities.     

食管癌转移的表观遗传学改变研究进展

食管癌的发生发展是基因变异和环境因素共同作用的结果,表观遗传学变化常受环境等后天因素调控,是食管癌复发和转移的关键驱动因素之一。本文综述参与食管癌发生和演进的表观遗传学变化,包括DNA甲基化、组蛋白修饰与染色质重塑、miRNA、长链非编码RNA等,分析总结表观遗传学变异在食管癌转移中的关键作用,为食管癌治疗提供新的思路和策略。     

Known epigenetic biomarkers for prostate cancer detection and management: exploring the potential of blood-based liquid biopsies

Introduction: Although prostate cancer (PCa) stands as an important cause of cancer-related deaths, a sizeable proportion of diagnosed cases are clinically insignificant. Hence, novel and more specific biomarkers to identify clinically significant PCa are needed. Liquid biopsies offer the potential to accurately identify cancer markers, including PCa. Epigenetic biomarkers such as cell-free DNA and circulating RNAs have emerged as minimally invasive cancer markers.

Areas covered: Herein, we provide an overview of epigenetic biomarkers current state based on a comprehensive review of the relevant literature in blood-based liquid biopsies and challenges/limitations of this new and growing field of cancer biomarkers.

Expert opinion: The epigenetic-based biomarkers characteristics make them attractive to the clinics and their minimally invasive assessment are a promising opportunity for PCa detection/management. The main limitations are the lack of robust validation studies and integrated approaches. Future studies would benefit from a change in focus to a ‘selected PCa detection’.     

SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis

Metastatic dissemination of breast cancer cells represents a significant clinical obstacle to curative therapy. The loss of function of metastasis suppressor genes is a major rate-limiting step in breast cancer progression that prevents the formation of new colonies at distal sites. However, the discovery of new metastasis suppressor genes in breast cancer using genomic efforts has been slow, potentially due to their primary regulation by epigenetic mechanisms. Here, we report the use of model cell lines with the same genetic lineage for the identification of a novel metastasis suppressor gene, serum deprivation response (SDPR), localized to 2q32-33, a region reported to be associated with significant loss of heterozygosity in breast cancer. In silico metaanalysis of publicly available gene expression datasets suggests that the loss of expression of SDPR correlates with significantly reduced distant-metastasis–free and relapse-free survival of breast cancer patients who underwent therapy. Furthermore, we found that stable SDPR overexpression in highly metastatic breast cancer model cell lines inhibited prosurvival pathways, shifted the balance of Bcl-2 family proteins in favor of apoptosis, and decreased migration and intravasation/extravasation potential, with a corresponding drastic suppression of metastatic nodule formation in the lungs of NOD/SCID mice. Moreover, SDPR expression is silenced by promoter DNA methylation, and as such it exemplifies epigenetic regulation of metastatic breast cancer progression. These observations highlight SDPR as a potential prognostic biomarker and a target for future therapeutic applications.The metastatic progression of breast cancer accounts for the majority of disease-related mortality. A major rate-limiting step in metastasis is the loss of function of the metastasis suppressor genes, which block a cascade of crucial steps including the loss of adhesion of primary tumor cells, intravasation into the blood and lymphatics with subsequent extravasation at distant sites, and the formation of new colonies. Despite the identification of the first metastasis suppressor gene, nonmetastatic 23 (NM23), nearly two decades ago (1), only a handful of new metastasis suppressors have been identified in recent years using candidate gene approaches (2, 3). It is likely that the current catalog of metastasis suppressor genes remains incomplete despite the vast sequencing efforts due to the possibility that a subset of genes regulated by epigenetic mechanisms may have eluded traditional discovery procedures (4–6). To identify these elusive metastasis suppressor genes, which are functionally compromised in late-stage disease (7–9), we took advantage of a well-established breast cancer progression cell line model system sharing the same genetic linage (Fig. 1A) (10). This model system consists of five cell lines that represent the various stages of breast cancer progression based on the MCF10A cell line: MCF10AneoT (NeoT), MCF10AT1Kcl2 (MII), MCF10CA1h (MIII), and MCF10CA1a (MIV). NeoT cells were generated by overexpression of HRAS in MCF10A cells and rarely exhibit growth following injection into nude mice. MII cells were generated by single xenograft passaging of NeoT cells. When injected subcutaneously (s.c.) into nude mice, MII cells generally form benign tumors that progress to carcinoma one out of four times; hence they mimic the early stage, carcinoma in situ. MIII and MIV cells were isolated from tumors formed by MII cells. MIII cells represent carcinoma, as in general they metastasize at a very low frequency, which requires a prolonged incubation period. On the other hand, MIV cells have the potential to readily seed lung metastases and represent the final stages of a breast cancer, metastatic carcinoma. We compared the gene expression profiles of these latter three model cell lines and leveraged large amounts of publically available breast tumor gene expression profiling data (11–13) by applying multiple bioinformatics filters to identify candidate metastasis suppressor genes.Open in a separate windowFig. 1.Identification of SDPR as a candidate metastasis suppressor gene. (A) Schematic depiction of the generation of breast cancer progression cell line model system. The model consists of five cell lines representing different stages of breast cancer progression. MI, normal breast epithelial cells; NeoT and MII, carcinoma in situ; MIII, carcinoma; and MIV, metastatic carcinoma. (B) Hierarchical clustering of gene expression profiles from MII, MIII, and MIV cells for the genes whose expression differ at least twofold between each cell line. Two clusters, cluster 6 and 7, are magnified because expressions of the genes in these two clusters are significantly suppressed in metastatic MIV cells compared with nonmetastatic MII and MIII. (C) The schematic summary of our strategy for the selection of SDPR as the top candidate metastasis suppressor.Here, we report the discovery of the phosphatidylserine-interacting protein, serum deprivation response (SDPR) (also known as cavin-2), as a bona fide metastasis suppressor. Thus far, studies on SDPR function have been limited to its role as a regulator of caveolae formation (14), and its potential direct involvement in cancer has not been previously described. However, it has been reported that SDPR expression is down-regulated significantly in not only breast cancer but also in cancers of kidney and prostate (15). Moreover, SDPR protein down-regulation was observed in serum from patients with malignant kidney tumors, and hence it was suggested as a possible diagnostic marker to discriminate malignant tumors from benign formations (16). Interestingly, SDPR is localized to 2q32-33, a region with a significant level of loss of heterozygosity that is associated with a high degree of recurrence in breast cancer (17, 18). Our results indicate that SDPR is capable of specifically inhibiting the metastatic growth of breast cancer cells.     

Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients

Recent studies suggest that genetic and environmental factors do not account for all the schizophrenia risk, and epigenetics also has a role in disease susceptibility. DNA methylation is a heritable epigenetic modification that can regulate gene expression. Genome-wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. After adjusting for age and post-mortem interval, 4641 probes corresponding to 2929 unique genes were found to be differentially methylated. Of those genes, 1291 were located in a CpG island and 817 were in a promoter region. These include NOS1, AKT1, DTNBP1, DNMT1, PPP3CC and SOX10, which have previously been associated with schizophrenia. More than 100 of these genes overlap with a previous DNA methylation study of peripheral blood from schizophrenia patients in which 27 000 CpG sites were analysed. Unsupervised clustering analysis of the top 3000 most variable probes revealed two distinct groups with significantly more people with schizophrenia in cluster one compared with controls (P=1.74 × 10⁻⁴). The first cluster composed of 88% of patients with schizophrenia and only 12% controls, whereas the second cluster composed of 27% of patients with schizophrenia and 73% controls. These results strongly suggest that differential DNA methylation is important in schizophrenia etiology and add support for the use of DNA methylation profiles as a future prognostic indicator of schizophrenia.