Fetal alcohol exposure alters proopiomelanocortin gene expression and hypothalamic-pituitary-adrenal axis function via increasing MeCP2 expression in the hypothalamus.
Fetal alcohol exposure alters proopiomelanocortin gene expression and hypothalamic-pituitary-adrenal axis function via increasing MeCP2 expression in the hypothalamus.
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DOI：
10.1371/journal.pone.0113228
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sarkar DK
中科院分区：
文献类型：
--
作者：
Gangisetty O;Bekdash R;Maglakelidze G;Sarkar DK
前阿黑皮素（Proopiomelanocortin，POMC）是下丘脑神经肽β-内啡肽的前体基因，参与调节包括应激反应在内的多种生理功能。最近的一些报告表明，胎儿酒精暴露程序下丘脑产生较低水平的POMC基因转录本，并提高下丘脑-垂体-肾上腺（HPA）轴对应激刺激的反应。我们研究了甲基CpG结合蛋白（MeCP 2）在产前乙醇对POMC基因表达和下丘脑-垂体-肾上腺（HPA）轴功能的影响中的作用。妊娠Sprague道利大鼠在GD 7 - 21期间喂食含6.7%酒精的流质饲料，配对喂食等热量流质饲料，或随意喂食大鼠饲料，其雄性后代在出生后60天用于本研究。胎儿酒精暴露降低了POMC mRNA的水平，但增加了下丘脑弓状核（ARC）中POMC神经元细胞体所在的该基因的DNA甲基化水平。暴露于酒精的胎鼠表现出POMC细胞中MeCP 2蛋白水平、MeCP 2基因转录水平以及弓状核中POMC启动子上MeCP 2蛋白结合的增加。慢病毒递送MeCP 2 shRNA进入第三脑室有效地降低了MeCP 2的表达，并阻止了产前乙醇对弓状核中POMC基因表达的影响。MeCP 2-shRNA治疗还使产前乙醇诱导的下丘脑促肾上腺皮质激素释放激素（CRH）基因表达增加以及血浆促肾上腺皮质激素（ACTH）和皮质酮激素对脂多糖（LPS）刺激的反应升高正常化。这些结果表明，POMC基因的胎儿酒精编程可能涉及招募MeCP 2到POMC基因的甲基化启动子上，以抑制POMC转录水平，并导致HPA轴失调。
Proopiomelanocortin (POMC) is a precursor gene of the neuropeptide β-endorphin in the hypothalamus and is known to regulate various physiological functions including stress response. Several recent reports showed that fetal alcohol exposure programs the hypothalamus to produce lower levels of POMC gene transcripts and to elevate the hypothalamic-pituitary-adrenal (HPA) axis response to stressful stimuli. We investigated the role of methyl CpG binding protein (MeCP2) in the effects of prenatal ethanol on POMC gene expression and hypothalamic-pituitary-adrenal (HPA) axis function. Pregnant Sprague Dawley rats were fed between GD 7 and 21 with a liquid diet containing 6.7% alcohol, pair-fed with isocaloric liquid diet, or fed ad libitum with rat chow, and their male offsprings were used at 60 days after birth in this study. Fetal alcohol exposure reduced the level of POMC mRNA, but increased the level of DNA methylation of this gene in the arcuate nucleus (ARC) of the hypothalamus where the POMC neuronal cell bodies are located. Fetal alcohol exposed rats showed a significant increase in MeCP2 protein levels in POMC cells, MeCP2 gene transcript levels as well as increased MeCP2 protein binding on the POMC promoter in the arcuate nucleus. Lentiviral delivery of MeCP2 shRNA into the third ventricle efficiently reduced MeCP2 expression and prevented the effect of prenatal ethanol on POMC gene expression in the arcuate nucleus. MeCP2-shRNA treatment also normalized the prenatal ethanol-induced increase in corticotropin releasing hormone (CRH) gene expression in the hypothalamus and elevated plasma adrenocorticotrophic hormone (ACTH) and corticosterone hormone responses to lipopolysaccharide (LPS) challenge. These results suggest that fetal alcohol programming of POMC gene may involve recruitment of MeCP2 on to the methylated promoter of the POMC gene to suppress POMC transcript levels and contribute to HPA axis dysregulation.
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影响因子：
25
作者：
Im, Heh-In;Hollander, Jonathan A.;Bali, Purva;Kenny, Paul J.
通讯作者：
Kenny, Paul J.
DOI：
10.1097/nen.0b013e3180302078
发表时间：
2007-02-01
影响因子：
3.2
作者：
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通讯作者：
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影响因子：
3.3
作者：
Kelley, Michelle L.;Braitman, Abby;Gumienny, Leslie
通讯作者：
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影响因子：
8.8
作者：
LISSONI, P;BARNI, S;TANCINI, G
通讯作者：
TANCINI, G
影响因子：
2.9
作者：
MILLER, MW
通讯作者：
MILLER, MW