HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis
Li Z. Luo, … , Cynthia L. Sears, Linda Resar
Li Z. Luo, … , Cynthia L. Sears, Linda Resar
Published February 3, 2025
Citation Information: J Clin Invest. 2025;135(3):e184442. https://doi.org/10.1172/JCI184442.
View: Text | PDF
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

×

Figure 8

Hmga1 deficiency alters cell state, decreasing stem and Paneth-like cell populations while expanding more differentiated cell populations in Apc deficient crypt cells.

Options: View larger image (or click on image) Download as PowerPoint
Hmga1 deficiency alters cell state, decreasing stem and Paneth-like cel...
(A) Pseudotime trajectory analysis estimated from scRNA-seq of CDX2P-CreERT2 Apcfl/fl crypt cells from the epithelial island with Hmga1+/+ or Hmga1–/–. HMGA1 deficient cells are more prominent in later stages of pseudotime (indicated by black ovals) compared with time 0 cells. (B) Cell states defined by the top 200 most differentially expressed genes on the trajectories from pseudotime analysis were assigned 0–4 and indicated by color on a trajectory plot (left) or bar graph (right). Note the skewing to cell states 3 and 4 in HMGA1 deficient cells. (C) Stem cells and enterocytes (ECs) imputed from scRNA-seq are shown on the trajectories to highlight the major differences between CDX2P-CreERT2 Apcfl/fl cells with intact HMGA1 or HMGA1 deficiency. HMGA1 deficient cells have increased ECs (blue) with decreased stem cells (violet). Bar graphs show relative cell frequencies (right); the top graphs show only stem and ECs, the bottom includes all cells with grey depicting cells that are not stem cells nor ECs.