HMGA1 amplifies Wnt signalling and expands the intestinal stem cell compartment and Paneth cell niche.
HMGA1 amplifies Wnt signalling and expands the intestinal stem cell compartment and Paneth cell niche.
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DOI：
10.1038/ncomms15008
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发表时间：
2017-04-28
影响因子：
16.6
通讯作者：
Resar LMS
中科院分区：
文献类型：
--
作者：
Xian L;Georgess D;Huso T;Cope L;Belton A;Chang YT;Kuang W;Gu Q;Zhang X;Senger S;Fasano A;Huso DL;Ewald AJ;Resar LMS
高迁移率族A1(HMGA1)染色质重塑蛋白富含在肠道干细胞(ISCs)中，尽管它们在这种环境中的功能尚不清楚。先前的研究表明，HMGA1导致转基因小鼠的过度增殖、异常隐窝形成和息肉病。在这里，我们证明了HMGA1放大Wnt/β-catenin信号转导，以增强自我更新和扩大ISC隔室。HMGA1上调编码Wnt激动剂受体和下游Wnt效应器的基因。HMGA1还通过扩大Paneth细胞室并直接诱导Paneth细胞分化所需的Sox9来帮助“建立”ISC生态位。在人类肠道中，HMGA1和SOX9呈正相关，在结直肠癌中两者均上调。我们的结果确定了HMGA1在肠道内稳态中的独特作用，它通过维持干细胞库和促进末端分化来建立上皮干细胞生态位。这项工作还表明，在肠道癌变过程中，解除调控的HMGA1扰乱了这种平衡。高迁移率族A1(HMGA1)染色质重塑蛋白在肠干细胞(ISC)中的功能尚不清楚。在这里，作者表明，HMGA1放大Wnt/β-catenin信号转导，以促进自我更新，并诱导Sox9扩大Paneth细胞室，丰富ISC生态位。
High-mobility group A1 (Hmga1) chromatin remodelling proteins are enriched in intestinal stem cells (ISCs), although their function in this setting was unknown. Prior studies showed that Hmga1 drives hyperproliferation, aberrant crypt formation and polyposis in transgenic mice. Here we demonstrate that Hmga1 amplifies Wnt/β-catenin signalling to enhance self-renewal and expand the ISC compartment. Hmga1 upregulates genes encoding both Wnt agonist receptors and downstream Wnt effectors. Hmga1 also helps to ‘build' an ISC niche by expanding the Paneth cell compartment and directly inducing Sox9, which is required for Paneth cell differentiation. In human intestine, HMGA1 and SOX9 are positively correlated, and both become upregulated in colorectal cancer. Our results define a unique role for Hmga1 in intestinal homeostasis by maintaining the stem cell pool and fostering terminal differentiation to establish an epithelial stem cell niche. This work also suggests that deregulated Hmga1 perturbs this equilibrium during intestinal carcinogenesis. The function of high mobility group A1 (Hmga1) chromatin remodelling proteins in intestinal stem cells (ISC) is unknown. Here, the authors show that Hmga1 amplifies Wnt/β-catenin signalling to enhance self-renewal and induces Sox9 to expand the Paneth cell compartment and enrich the ISC niche.