High Mobility Group A1 Chromatin Remodeling Protein Expands The Intestinal Stem Cell Compartment And Paneth Cell Niche Through Wnt/Beta-Catenin Signaling And Sox9

The High Mobility Group A1 (HMGA1) gene is overexpressed in most poorly differentiated cancers and high levels portend adverse clinical outcomes, although the molecular mechanisms through which it functions are poorly understood. HMGA1 encodes the HMGA1a and HMGA1b chromatin remodeling proteins, which modulate gene expression by bending chromatin and orchestrating the assembly of transcription factor complexes to DNA. HMGA1 is highly expressed during embryogenesis, but silenced in adult, differentiated tissues. Postnatally, HMGA1 expression is maintained in adult stem cells, such as intestinal stem cells (ISCs); however, its role in this setting has been unknown. Here, we report that Hmga1 overexpression in ISCs of transgenic mice drives expansion in the ISC compartment leading to hyperproliferation, aberrant crypt formation, and polyposis. Surprisingly, Hmga1 transgenic mice also exhibit marked expansion in terminally differentiated Paneth cells, which comprise an epithelial cell niche for ISCs. To dissect the mechanisms mediating these phenotypes, we generated three-dimensional (3D) intestinal organoids with varied expression of Hmga1. Strikingly, silencing Hmga1 in wildtype crypt cells disrupts their ability to organize into functional 3D organoids with bud formation, while crypt cells expressing ectopic Hmga1 exhibit enhanced organoid formation with increased ISC number, proliferation, and bud development. Because Wnt/β-catenin signaling is central to ISC function, we determined whether Hmga1 modulates this pathway. β-catenin protein is increased in the crypts of the Hmga1 transgenic mice and organoids. Hmga1 amplifies Wnt/β-catenin signaling by inducing both genes that encode Wnt cell surface receptors and target genes downstream of Wnt/β-catenin. Hmga1 also directly up-regulates Sox9, which is required for terminal differentiation to Paneth cells. This is the first example of Hmga1 fostering terminal differentiation to establish a stem cell niche. In human intestinal epithelium, HMGA1 and SOX9 are highly correlated (P = 0.008), and both become up-regulated in carcinogenesis. These results reveal a novel role for Hmga1 in intestinal homeostasis by maintaining both the stem cell pool and epithelial niche compartment and suggest that deregulated Hmga1 perturbs this equilibrium during intestinal carcinogenesis. Citation Format: Lingling Xian, Tait Huso, Amy Belton, David Huso, Linda M. S. Resar. High mobility group A1 chromatin remodeling protein expands the intestinal stem cell compartment and Paneth cell niche through Wnt/β-catenin signaling and Sox9. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1704.