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 J. Ewald and Linda M. S. Resar ()
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Lingling Xian: The Johns Hopkins University School of Medicine
Dan Georgess: The Johns Hopkins University School of Medicine
Tait Huso: The Johns Hopkins University School of Medicine
Leslie Cope: The Johns Hopkins University School of Medicine
Amy Belton: The Johns Hopkins University School of Medicine
Yu-Ting Chang: Pathobiology Graduate Program, The Johns Hopkins University School of Medicine
Wenyong Kuang: The Johns Hopkins University School of Medicine
Qihua Gu: The Johns Hopkins University School of Medicine
Xiaoyan Zhang: The Johns Hopkins University School of Medicine
Stefania Senger: Mucosal Immunology and Biology Research Center, Harvard Medical School, Massachusetts General Hospital East
Alessio Fasano: Mucosal Immunology and Biology Research Center, Harvard Medical School, Massachusetts General Hospital East
David L. Huso: The Johns Hopkins University School of Medicine
Andrew J. Ewald: The Johns Hopkins University School of Medicine
Linda M. S. Resar: The Johns Hopkins University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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 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.

Date: 2017
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DOI: 10.1038/ncomms15008

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