VGLL4 modulates Paneth cells and sustains intestinal homeostasis
Paneth cells are defensive cells in the intestinal tract, which secrete niche factors and antimicrobial peptides (AMPs) to maintain the small intestinal stem cell niche and immune homeostasis. Here, we show that Vestigial-like family member 4 (VGLL4) plays a pivotal role in maintaining small intestinal homeostasis and in regulating Paneth cells. VGLL4 expression is downregulated in response to irradiation and DSS-induced colitis. Consistently, public datasets of human colitis show reduced VGLL4 expression. Loss of VGLL4 in the intestinal epithelium decreases Paneth cell numbers and AMPs production, and triggers gut microbiota dysbiosis, impairing intestinal regenerative capacity. Mechanistically, VGLL4 forms a complex with TEAD4 and ATOH1, stimulating GFI1 expression and promoting Paneth cell differentiation. Furthermore, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining microbiota composition. Collectively, our findings uncover novel roles for VGLL4 in intestinal homeostasis.
Authors
- Haoen Zhang (ORCID: https://orcid.org/0009-0008-9824-6776)
- Zuoyun Wang (ORCID: https://orcid.org/0000-0003-4428-5477)
- Zhonghua Cheng
- Ruizeng Yang
- Jinjin Xu
- Shuo Huang
- Hu Zhou
- Jinsong Li
- Tiantian Lu
- Jing Yu (ORCID: https://orcid.org/0000-0002-6646-9341)
- Xiaoyu Li
- Jiale Ren
- Wentao Yu
- Lei Zhang
- Jiaqi Sun
- Fang Wei
- Yi Lu (ORCID: https://orcid.org/0000-0002-1060-6925)
- Nan Tang
- Yang Sun
- Xiaodong Wang (ORCID: https://orcid.org/0000-0002-0986-373X)
- Jun Qin
- Xueyan Ma
- Haijiao Zhang
- Guoying Zhang
- Yunyun Jin
Institutions
- Shanghai Medical College of Fudan University (CN)
- Shanghai Jiao Tong University (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Shanghai Institute of Materia Medica (CN)
- Shanghai Xuhui Central Hospital (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Pudong Medical Center (CN)
- Institute for Advanced Study (DE)
- Shanghai Sixth People's Hospital (CN)
- Shanghai Jian Qiao University (CN)
- Center for Life Sciences (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-02-02
- DOI
- https://doi.org/10.1038/s44319-026-00699-3
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 22.24
Funders
- National Natural Science Foundation of China
- Shanghai Jiao Tong University
- National Key Research and Development Program of China