HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis
Li Z. Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E. West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L. Reddy, Ying Feng, Eric R. Fearon, Cynthia L. Sears, Linda Resar
Li Z. Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E. West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L. Reddy, Ying Feng, Eric R. Fearon, Cynthia L. Sears, Linda Resar
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Research Article Oncology

HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis

Abstract

Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 “opens” chromatin to upregulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas reexpression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.

Authors

Li Z. Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E. West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L. Reddy, Ying Feng, Eric R. Fearon, Cynthia L. Sears, Linda Resar

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Figure 9

HMGA1 activates gene networks within the crypt epithelial island involved in IFN signaling, inflammation, DNA repair, proliferation, and Wnt signaling.

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HMGA1 activates gene networks within the crypt epithelial island involve...
(A) GSEA analysis (left) of single cell transcripts from the epithelial island reveals that HMGA1 activates pathways involved in inflammation (IFN-α, IFN-γ), DNA repair, and proliferation (MYC) while repressing pathways active in differentiated ECs (fatty acid metabolism, protein secretion); FDR ≤ 0.25. Enrichment plots (right) show HMGA1 networks in more detail, including genes involved in inflammation (IFN-α), DNA repair, and Wnt signaling. Normalized enrichment score (NES) and normalized P values are indicated. (B) IFN-inducible genes that mediate inflammatory signals, including IFN-induced transmembrane 1, 2, 3, (Ifitm1, 2, 3) genes, IFN stimulated gene 15 (Isg15), Stat1, Stat2, and cytokines (Ccl5, Cxcl9, Cxcl10) are activated by HMGA1. Dot plots depict gene expression (–0.4 to +0.4) and the proportion of cells (25%–75%) expressing each transcript within the epithelial island.