Sex-Determining Region Y Controls the Effects of Fetal Alcohol Exposure on Proopiomelanocortin Gene Expression.
Sex-Determining Region Y Controls the Effects of Fetal Alcohol Exposure on Proopiomelanocortin Gene Expression.
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DOI：
10.3389/fnins.2021.608102
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发表时间：
2021
影响因子：
4.3
通讯作者：
Sarkar DK
中科院分区：
文献类型：
--
作者：
Gangisetty O;Mead EA;Sarkar DK
胎儿酒精暴露（FAE）导致后代的各种神经发育缺陷，包括压力调节proopiomelanocortin（Pomc）基因的表达减少和通过雄性生殖系多代人的应激反应升高。FAE对Pomc基因的男性生殖系特异性影响提出了性别决定区Y（SRY）是否可能在调节Pomc基因表达中发挥作用的问题。使用Fischer 344大鼠FAE的跨代模型，我们确定了SRY在Pomc基因调控中的作用。与Pomc基因一样，FAE降低了雄性成年后代精子和下丘脑中基底核（MBH）的Sry基因表达。胎儿酒精诱导的Sry基因表达抑制与Sry启动子DNA甲基化增加有关。此外，胎儿酒精对Sry基因的影响在男性生殖系中持续了三代，但在女性生殖系中没有。Sry基因敲除降低了Pomc基因的表达。与对照组大鼠相比，暴露于酒精的胎鼠下丘脑中Pomc启动子上的Sry募集被发现减少。Pomc启动子荧光素酶活性在Sry过表达后增加。定点突变研究表明，SRY结合位点是POMC启动子转录活性所必需的。总体而言，这些研究结果表明，SRY在Pomc基因表达的调节中起着刺激作用，并可能有助于胎儿酒精诱导的多代Pomc基因表达水平的变化。
Fetal alcohol exposure (FAE) causes various neurodevelopmental deficits in offspring, including reduced expression of the stress regulatory proopiomelanocortin (Pomc) gene and an elevated stress response for multiple generations via the male germline. Male germline-specific effects of FAE on the Pomc gene raises the question if the sex-determining region Y (SRY) may have a role in regulating Pomc gene expression. Using a transgenerational model of FAE in Fischer 344 rats, we determined the role of SRY in the regulation of the Pomc gene. FAEs, like on the Pomc gene, reduced Sry gene expression in sperm and the mediobasal hypothalamus (MBH) in male adult offspring. Fetal alcohol-induced inhibition of Sry gene expression was associated with increased Sry promoter DNA methylation. Additionally, fetal alcohol effects on the Sry gene persisted for three generations in the male germline but not in the female germline. Sry gene knockdown reduced the Pomc gene expression. Sry recruitment onto the Pomc promoter was found to be reduced in the hypothalamus of fetal alcohol-exposed rats compared to control rats. Pomc promoter luciferase activity was increased following Sry overexpression. A site-directed mutagenesis study revealed that SRY binding sites are required for POMC promoter transcription activity. Overall, these findings suggest that SRY plays a stimulatory role in the regulation of Pomc gene expression and may potentially contribute to the fetal alcohol-induced changes in the level of Pomc gene expression for multiple generations.
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基本的螺旋 - 环螺旋转录因子TCF21是确定基因SRY的男性性别的下游靶标。
影响因子：
3.7
作者：
Bhandari RK;Sadler-Riggleman I;Clement TM;Skinner MK
通讯作者：
Skinner MK
影响因子：
3.7
作者：
Gangisetty O;Bekdash R;Maglakelidze G;Sarkar DK
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Sarkar DK
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通讯作者：
MILLER, MW
影响因子：
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通讯作者：
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影响因子：
9.2
作者：
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通讯作者：
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