Jonckheere Nicolas, Vincent Audrey, Franquet-Ansart Hélène, Witte-Bouma Janneke, Korteland-van Male Anita, Leteurtre Emmanuelle, Renes Ingrid B, Van Seuningen Isabelle
Jean Pierre Aubert Research Center, Lille cedex, France.
Biochim Biophys Acta. 2012 Aug;1819(8):869-76. doi: 10.1016/j.bbagrm.2012.04.003. Epub 2012 Apr 25.
During human embryonic and fetal development of the gastrointestinal tract, the gene encoding the MUC5AC mucin has a spatio-temporal pattern of expression restricted to the stomach. In order to better understand the molecular mechanisms responsible for this restricted pattern of expression, we have studied Muc5ac expression in the developing stomach of the mouse and correlated it to that of transcription factors known to be involved in cell differentiation programs during development. Our results indicate that GATA-6 and HNF-4α expression increased concomitantly with the induction of Muc5ac expression in embryonic stomach. We then studied Muc5ac transcriptional regulation by these transcription factors and showed that they all transactivate Muc5ac promoter. We also identified several active GATA-4/-5/-6 and HNF-1/-4 cis-elements using gel shift assays, chromatin immunoprecipitation and site-directed mutagenesis. Among all Muc5ac regulators, only GATA-6 and HNF-4a expression was concomitant to that of Muc5ac in the developing stomach. This is thus in favor of an important role for these two transcription factors as regulators of expression of the Muc5ac mucin during stomach development and in epithelial cancer cells.
在人类胃肠道胚胎和胎儿发育过程中，编码MUC5AC粘蛋白的基因具有仅限于胃的时空表达模式。为了更好地理解造成这种受限表达模式的分子机制，我们研究了Muc5ac在小鼠发育中的胃中的表达，并将其与已知参与发育过程中细胞分化程序的转录因子的表达相关联。我们的结果表明，在胚胎胃中，GATA-6和HNF-4α的表达随着Muc5ac表达的诱导而同步增加。然后我们研究了这些转录因子对Muc5ac的转录调控，结果表明它们均能反式激活Muc5ac启动子。我们还通过凝胶迁移试验、染色质免疫沉淀和定点诱变鉴定了几个活性GATA-4/-5/-6和HNF-1/-4顺式元件。在所有Muc5ac调节因子中，只有GATA-6和HNF-4α的表达与发育中的胃中Muc5ac的表达同步。因此，这支持了这两种转录因子在胃发育和上皮癌细胞中作为Muc5ac粘蛋白表达调节因子的重要作用。
