Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland 21205, USA.
Department of Cell Biology, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, USA.
Nat Commun. 2017 Apr 28;8:15008. doi: 10.1038/ncomms15008.
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.
高迁移率族蛋白 A1（Hmga1）染色质重塑蛋白在肠干细胞（ISCs）中丰富，但它们在这种情况下的功能尚不清楚。先前的研究表明，Hmga1 驱动转基因小鼠过度增殖、异常隐窝形成和息肉形成。在这里，我们证明 Hmga1 放大了 Wnt/β-catenin 信号，以增强自我更新并扩大 ISC 隔室。Hmga1 上调编码 Wnt 激动剂受体和下游 Wnt 效应物的基因。Hmga1 还通过扩大潘氏细胞隔室并直接诱导 Sox9 来帮助“构建”ISC 生态位，Sox9 是潘氏细胞分化所必需的。在人类肠道中，HMGA1 和 SOX9 呈正相关，并且在结直肠癌中均上调。我们的研究结果通过维持干细胞池和促进终末分化来建立上皮干细胞生态位，定义了 Hmga1 在肠道稳态中的独特作用。这项工作还表明，失调的 Hmga1 在肠道癌变过程中破坏了这种平衡。
