HMGA1 amplifies Wnt signalling and expands the intestinal stem cell compartment and Paneth cell niche

Lingling Xian, Dan Georgess, Tait Huso, Leslie Cope, Amy Belton, Yu Ting Chang, Wenyong Kuang, Qihua Gu, Xiaoyan Zhang, Stefania Senger, Alessio Fasano, David L. Huso, Andrew Ewald, Linda M Smith Resar

Research output: Contribution to journalArticle

Abstract

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 selfrenewal 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.

Original languageEnglish (US)
Article number15008
JournalNature Communications
Volume8
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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