Novel DNA methylation profiles associated with key gene regulation and transcription pathways in blood and placenta of growth-restricted neonates.
Novel DNA methylation profiles associated with key gene regulation and transcription pathways in blood and placenta of growth-restricted neonates.
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与关键基因调节和转录途径相关的新型DNA甲基化谱在生长限制的新生儿的血液和胎盘中。
DOI：
10.4161/15592294.2014.989741
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Williams DJ
中科院分区：
文献类型：
--
作者：
Hillman SL;Finer S;Smart MC;Mathews C;Lowe R;Rakyan VK;Hitman GA;Williams DJ
胎儿的发育是由胎儿胎盘基因组与母体在宫内环境中的相互作用决定的。这种相互作用的失败会导致胎盘发育不良和胎儿生长受限(FGR)，这与未来的代谢性疾病有关。我们调查了脐带血和胎盘中是否存在全基因组甲基化的差异，在妊娠匹配、FGR和适当生长(AGA)的新生儿之间。使用Infinium HumanMylation450 BeadChip®，我们发现足月出生的FGR(n=19)的脐带血DNA有839个差异甲基化位置(DMP)，与AGA(n=18)相比达到了全基因组意义。使用胎龄作为一个连续变量，我们在脐带血中识别出76,249个DMP(adj.P<；0.05)，其中121个DMP是839个DMP中常见的，当比较12个FGR和12个AGA时仍然明显[分别为39.9±1.2周和40.0±1.0周(平均±标准差)]。共有53个DMP有10%的β甲基化差异，25个基因在1,000个碱基对中有两次以上的共甲基化。DMP的基因本体论(GO)分析支持它们参与与器官发育和代谢功能相关的基因调控和转录途径。在脐带血中的不同细胞类型中也发现了相似的DMPs图谱。在TERM阶段，FGR和AGA胎盘之间的DMP没有达到全基因组意义，并通过外部数据集进行了验证。对284例早产、胎盘DMP与自噬、氧化应激和激素反应相关的GO分析。生长受限新生儿出生时在早产胎盘和脐带血中有不同的DNA甲基化特征，这可能是未来成人疾病的易感因素。
Fetal growth is determined by the feto-placental genome interacting with the maternal in utero environment. Failure of this interplay leads to poor placental development and fetal growth restriction (FGR), which is associated with future metabolic disease. We investigated whether whole genome methylation differences existed in umbilical cord blood and placenta, between gestational-matched, FGR, and appropriately grown (AGA) neonates. Using the Infinium HumanMethylation450 BeadChip®, we found that DNA from umbilical cord blood of FGR born at term (n = 19) had 839 differentially methylated positions (DMPs) that reached genome-wide significance compared with AGA (n = 18). Using gestational age as a continuous variable, we identified 76,249 DMPs in cord blood (adj. P < 0.05) of which 121 DMPs were common to the 839 DMPs and were still evident when comparing 12 FGR with 12 AGA [39.9 ± 1.2 vs. 40.0 ± 1.0 weeks (mean ± SD), respectively]. A total of 53 DMPs had a β methylation difference >10% and 25 genes were co-methylated more than twice within 1000 base pairs. Gene Ontology (GO) analysis of DMPs supported their involvement in gene regulation and transcription pathways related to organ development and metabolic function. A similar profile of DMPs was found across different cell types in the cord blood. At term, no DMPs between FGR and AGA placentae reached genome-wide significance, validated with an external dataset. GO analysis of 284 pre-term, placental DMPs associated with autophagy, oxidative stress and hormonal responses. Growth restricted neonates have distinct DNA methylation profiles in pre-term placenta and in cord blood at birth, which may predispose to future adult disease.