GATA4 Is Sufficient to Establish Jejunal Versus Ileal Identity in the Small Intestine.
GATA4 Is Sufficient to Establish Jejunal Versus Ileal Identity in the Small Intestine.
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DOI：
10.1016/j.jcmgh.2016.12.009
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发表时间：
2017-05
影响因子：
7.2
通讯作者：
Battle MA
中科院分区：
文献类型：
--
作者：
Thompson CA;Wojta K;Pulakanti K;Rao S;Dawson P;Battle MA
小肠上皮沿其头尾轴的图案形成了三个功能不同的区域：十二指肠、空肠和回肠。有效的营养同化和生长依赖于十二指肠、空肠和回肠肠细胞执行的特殊消化和吸收功能的适当空间模式。当肠道细胞功能因疾病或损伤而被扰乱时，可能会发生肠衰竭。缓解肠道衰竭的一种方法是恢复失去的肠道细胞功能。然而，决定区域定义的肠细胞功能的分子机制并未得到很好的描述。我们先前已经证明GATA结合蛋白4(GATA4)是定义空肠肠细胞所必需的。这项研究的目的是验证GATA4足以在肠上皮内赋予空肠特性的假设。为了验证这一假设，我们建立了一个新的GATA4条件性敲入小鼠系，并在缺乏GATA4的回肠组织中表达了GATA4。我们发现表达GATA4的回肠失去了回肠身份。表达GATA4的回肠上皮的整体基因表达谱更接近于空肠和十二指肠，而不是回肠。针对空肠和回肠的同一性，我们定义了一组可能受GATA4直接调控的空肠和回肠基因，以抑制回肠同一性和促进空肠同一性。此外，我们的研究表明，GATA4是成纤维细胞生长因子15(Fgf15)的转录抑制因子，Fgf15编码的肠因子与越来越多的人类疾病有关。总体而言，本研究通过阐述GATA4的S功能作为空肠肠细胞特性的关键主导分子决定因素，加深了我们对GATA4依赖的沿头尾轴形成肠上皮模式的重要分子机制的理解。这项研究的微阵列数据已被存入美国国家生物信息学研究所基因表达总览(http://www.ncbi.nlm.nih.gov/geo))，并可通过GEO系列注册号GSE75870获取。
Patterning of the small intestinal epithelium along its cephalocaudal axis establishes three functionally distinct regions: duodenum, jejunum, and ileum. Efficient nutrient assimilation and growth depend on the proper spatial patterning of specialized digestive and absorptive functions performed by duodenal, jejunal, and ileal enterocytes. When enterocyte function is disrupted by disease or injury, intestinal failure can occur. One approach to alleviate intestinal failure would be to restore lost enterocyte functions. The molecular mechanisms determining regionally defined enterocyte functions, however, are poorly delineated. We previously showed that GATA binding protein 4 (GATA4) is essential to define jejunal enterocytes. The goal of this study was to test the hypothesis that GATA4 is sufficient to confer jejunal identity within the intestinal epithelium. To test this hypothesis, we generated a novel Gata4 conditional knock-in mouse line and expressed GATA4 in the ileum, where it is absent. We found that GATA4-expressing ileum lost ileal identity. The global gene expression profile of GATA4-expressing ileal epithelium aligned more closely with jejunum and duodenum rather than ileum. Focusing on jejunal vs ileal identity, we defined sets of jejunal and ileal genes likely to be regulated directly by GATA4 to suppress ileal identity and promote jejunal identity. Furthermore, our study implicates GATA4 as a transcriptional repressor of fibroblast growth factor 15 (Fgf15), which encodes an enterokine that has been implicated in an increasing number of human diseases. Overall, this study refines our understanding of an important GATA4-dependent molecular mechanism to pattern the intestinal epithelium along its cephalocaudal axis by elaborating on GATA4’s function as a crucial dominant molecular determinant of jejunal enterocyte identity. Microarray data from this study have been deposited into NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) and are accessible through GEO series accession number GSE75870.