Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells.
Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells.
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DOI：
10.1016/j.scr.2014.03.009
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发表时间：
2014-05
影响因子：
1.2
通讯作者：
Kim, Yong
中科院分区：
文献类型：
--
作者：
Khalid, Omar;Kim, Jeffrey J.;Kim, Hyun-Sung;Hoang, Michael;Tu, Thanh G.;Elie, Omid;Lee, Connie;Vu, Catherine;Horvath, Steve;Spigelman, Igor;Kim, Yong
干细胞，特别是人类胚胎干细胞（hESCs），是研究人类妊娠期疾病分子机制的有用模型。怀孕期间摄入酒精（乙醇，EtOH）会导致各种产前和产后疾病，统称为胎儿酒精谱系障碍（FASDs）。为了更好地了解导致fasd的分子事件，我们对EtOH对培养hESCs维持和分化的影响进行了全基因组分析。基因共表达网络分析显示，etoh处理的分化或未分化hESCs的基因谱发生了显著变化，特别是那些与代谢过程、氧化应激和干细胞神经元特性的分子途径相关的基因谱。一项全基因组DNA甲基组分析显示，etoh诱导的改变广泛存在，染色体的许多区域都出现了显著的高甲基化。未分化的hESCs比已分化的hESCs更容易受到EtOH的影响，在未分化的hESCs中，2、16和18染色体启动子区域的甲基化受EtOH的影响最大。结合转录组学和DNA甲基化组学分析得出了一系列分化相关基因被etoh诱导的DNA甲基化改变失调，这可能在etoh诱导的hESC多能性降低中起作用。对EtOH改变的基因进行DNA序列基序分析，确定了代表转录因子潜在结合位点的主要基序。这些发现应该有助于破译酒精诱导的致畸的确切机制。
Stem cells, especially human embryonic stem cells (hESCs), are useful models to study molecular mechanisms of human disorders that originate during gestation. Alcohol (ethanol, EtOH) consumption during pregnancy causes a variety of prenatal and postnatal disorders collectively referred to as fetal alcohol spectrum disorders (FASDs). To better understand the molecular events leading to FASDs, we performed a genome-wide analysis of EtOH's effects on the maintenance and differentiation of hESCs in culture. Gene Co-expression Network Analysis showed significant alterations in gene profiles of EtOH-treated differentiated or undifferentiated hESCs, particularly those associated with molecular pathways for metabolic processes, oxidative stress, and neuronal properties of stem cells. A genome-wide DNA methylome analysis revealed widespread EtOH-induced alterations with significant hypermethylation of many regions of chromosomes. Undifferentiated hESCs were more vulnerable to EtOH's effect than their differentiated counterparts, with methylation on the promoter regions of chromosomes 2, 16 and 18 in undifferentiated hESCs most affected by EtOH exposure. Combined transcriptomic and DNA methylomic analysis produced a list of differentiation-related genes dysregulated by EtOH-induced DNA methylation changes, which likely play a role in EtOH-induced decreases in hESC pluripotency. DNA sequence motif analysis of genes epigenetically altered by EtOH identified major motifs representing potential binding sites for transcription factors. These findings should help in deciphering the precise mechanisms of alcohol-induced teratogenesis.
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DOI：
10.1111/j.1530-0277.1998.tb05913.x
发表时间：
1998-12-01
期刊：
ALCOHOL-CLINICAL AND EXPERIMENTAL RESEARCH
影响因子：
--
作者：
Foroud, T;Bucholz, KK;Begleiter, H
通讯作者：
Begleiter, H
影响因子：
2.8
作者：
Anthony, Bruce;Zhou, Feng C.;Ruiz, Joseph
通讯作者：
Ruiz, Joseph
DOI：
10.1016/j.bbrc.2008.03.060
发表时间：
2008-05-23
影响因子：
3.1
作者：
Fujita, Yuko;Hiroyama, Masami;Tanoue, Akito
通讯作者：
Tanoue, Akito
DOI：
10.1111/j.1530-0277.2002.tb02544.x
发表时间：
2002-03-01
影响因子：
3.2
作者：
Bielawski, DM;Zaher, FM;Abel, EL
通讯作者：
Abel, EL
DOI：
10.1111/j.1530-0277.1991.tb00536.x
发表时间：
1991-06-01
影响因子：
3.2
作者：
GARRO, AJ;MCBETH, DL;LIEBER, CS
通讯作者：
LIEBER, CS