Examining How the MAFB Transcription Factor Affects Islet -Cell Function Postnatally
Examining How the MAFB Transcription Factor Affects Islet -Cell Function Postnatally
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DOI：
10.2337/db18-0903
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发表时间：
2019-02-01
期刊：
影响因子：
7.7
通讯作者：
Stein, Roland
中科院分区：
文献类型：
--
作者：
Cyphert, Holly A.;Walker, Emily M.;Stein, Roland
MAFB转录因子在人胰岛细胞中的持续表达在小鼠中表现出明显的差异。此外，密切相关的富含胰岛细胞的MAFA的mRNA在人类中的表达直到9岁以后才达到峰值。我们发现MAFA蛋白在幼年人类胰岛细胞群中也有微弱的产生，而MafB蛋白在小鼠细胞中的表达在出生后受到从头DNA甲基化的限制。为了深入了解MAFB如何影响人类细胞，我们开发了一个小鼠模型，使用MAFA转录控制序列在成年小鼠细胞中异位表达MafB。MafB和MafA共表达对小鼠细胞无明显影响，提示人成体细胞MAFA/MAFB异源二聚体与小鼠MafA同源二聚体在功能上是相同的。然而，MafB本身并不能挽救缺乏MafA in-cell的小鼠突变的胰岛细胞缺陷。值得注意的是，转基因生产的MafB细胞内增加了怀孕期间色氨酸羟基酶1mRNA的产生，这推动了5-羟色胺的生物合成，这对母体细胞的适应性反应至关重要。总之，这些研究为MAFB在人类胰岛细胞中的作用提供了新的见解。
The sustained expression of the MAFB transcription factor in human islet -cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet -cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet -cell population and that MafB expression is postnatally restricted in mouse -cells by de novo DNA methylation. To gain insight into how MAFB affects human -cells, we developed a mouse model to ectopically express MafB in adult mouse -cells using MafA transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse -cells, suggesting that the human adult -cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet -cell defects in a mouse mutant lacking MafA in -cells. Of note, transgenic production of MafB in -cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal -cell responses. Together, these studies provide novel insight into the role of MAFB in human islet -cells.