Human fetoplacental arterial and venous endothelial cells are differentially programmed by gestational diabetes mellitus, resulting in cell-specific barrier function changes.
Human fetoplacental arterial and venous endothelial cells are differentially programmed by gestational diabetes mellitus, resulting in cell-specific barrier function changes.
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DOI：
10.1007/s00125-018-4699-7
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发表时间：
2018-11
期刊：
影响因子：
8.2
通讯作者：
Hiden U
中科院分区：
文献类型：
--
作者：
Cvitic S;Novakovic B;Gordon L;Ulz CM;Mühlberger M;Diaz-Perez FI;Joo JE;Svendova V;Schimek MG;Trajanoski S;Saffery R;Desoye G;Hiden U
不利的宫内环境可导致后代生理学的永久性变化，并使其成年后易患疾病。妊娠期糖尿病（GDM）是一种此类暴露，与后代代谢紊乱和心血管疾病的发展有关。表观遗传变异，包括DNA甲基化，被认为是支撑胎儿编程的主要机制，我们假设这在暴露于GDM后的胎儿胎盘内皮功能障碍中起关键作用。因此，我们进行了一项初步的表观遗传学研究，以分析一致的DNA甲基化和基因表达的变化，在GDM暴露的胎儿胎盘内皮细胞。来自健康妊娠和GDM并发妊娠的原代胎儿胎盘动脉内皮细胞（AEC）和静脉内皮细胞（VEC）的全基因组甲基化分析与转录组分析平行，确定了甲基化和表达变化。最受影响的途径和功能，确定了有害途径分析，并使用功能测定验证。转录组和甲基化分析确定了与AEC中408个基因和VEC中159个基因中GDM相关DNA甲基化相关的基因表达变异，这意味着直接的功能联系。通路分析发现，暴露于GDM改变的基因聚集在健康AEC和VEC中与“细胞形态”和“细胞运动”相关的功能。进一步的功能分析表明，GDM暴露的细胞改变了肌动蛋白组织和屏障功能。我们的数据表明，暴露于GDM程序非典型形态和屏障功能的胎儿胎盘内皮细胞的DNA甲基化和基因表达的变化。AEC和VEC之间的影响不同，表明严格的细胞特异性敏感性与子宫内发育编程相关的不良暴露。本研究期间生成和分析的DNA甲基化和基因表达数据集可分别在国家生物技术信息中心（NCBI）基因表达综合（GEO）数据库（http：//www.ncbi.nlm.nih.gov/geo）获得，登录号为GSE106099和GSE103552。本文的在线版本（10.1007/s00125 - 018 - 4699 - 7）包含同行评审但未经编辑的补充材料，可供授权用户使用。
An adverse intrauterine environment can result in permanent changes in the physiology of the offspring and predispose to diseases in adulthood. One such exposure, gestational diabetes mellitus (GDM), has been linked to development of metabolic disorders and cardiovascular disease in offspring. Epigenetic variation, including DNA methylation, is recognised as a leading mechanism underpinning fetal programming and we hypothesised that this plays a key role in fetoplacental endothelial dysfunction following exposure to GDM. Thus, we conducted a pilot epigenetic study to analyse concordant DNA methylation and gene expression changes in GDM-exposed fetoplacental endothelial cells. Genome-wide methylation analysis of primary fetoplacental arterial endothelial cells (AEC) and venous endothelial cells (VEC) from healthy pregnancies and GDM-complicated pregnancies in parallel with transcriptome analysis identified methylation and expression changes. Most-affected pathways and functions were identified by Ingenuity Pathway Analysis and validated using functional assays. Transcriptome and methylation analyses identified variation in gene expression linked to GDM-associated DNA methylation in 408 genes in AEC and 159 genes in VEC, implying a direct functional link. Pathway analysis found that genes altered by exposure to GDM clustered to functions associated with ‘cell morphology’ and ‘cellular movement’ in healthy AEC and VEC. Further functional analysis demonstrated that GDM-exposed cells had altered actin organisation and barrier function. Our data indicate that exposure to GDM programs atypical morphology and barrier function in fetoplacental endothelial cells by DNA methylation and gene expression change. The effects differ between AEC and VEC, indicating a stringent cell-specific sensitivity to adverse exposures associated with developmental programming in utero. DNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively. The online version of this article (10.1007/s00125-018-4699-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
16.2
作者：
Friedman JE
通讯作者：
Friedman JE
影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
7.7
作者：
Cheng X;Chapple SJ;Patel B;Puszyk W;Sugden D;Yin X;Mayr M;Siow RC;Mann GE
通讯作者：
Mann GE
影响因子：
6.6
作者：
Lang, I;Pabst, MA;Desoye, G
通讯作者：
Desoye, G
影响因子：
5.8
作者：
Aryee, Martin J.;Jaffe, Andrew E.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.