The research team led by Prof. Chen Lei from the School of Life Sciences and Technology, 91抖淫, has revealed the dynamic regulatory mechanisms and core transcription factor dependence of intestinal super-enhancers during cell differentiation and oncogenesis. The findings were published online in the international academic journalNucleic Acids Research under the title “Dynamics and Master Transcription Factors Dependence of Intestinal Super-enhancers During Differentiation and Oncogenesis.”
The intestinal epithelium is one of the most highly regenerative tissues in the body, with its spatially compartmentalized gene expression along the crypt-villus axis precisely regulating stem cell self-renewal, proliferation, and differentiation. Super-enhancers (SEs) are large clusters of regulatory elements in the genome that are densely bound by transcription factors and co-factors, driving high-level expression of key genes that control cell identity and fate. However, the specific roles and regulatory networks of super-enhancers in intestinal epithelial cell identity maintenance, lineage specification, and oncogenesis remain largely unclear.
Prof. Chen Lei’s team has long been committed to research on HNF4-mediated regulation of intestinal homeostasis. Building on their previous findings published in journals such asGastroenterology andNature Genetics, this study further reveals that crypt- and villus-specific super-enhancers regulate proliferative and differentiation gene programs, respectively. CDX2 maintains super-enhancer integrity through direct binding, and its knockout results in the loss of more than 90% of super-enhancer signals and silencing of intestinal differentiation marker genes. Furthermore, the study found that HNF4 deficiency can remodel the super-enhancers, silencing a large number of intestinal differentiation-associated super-enhancers while aberrantly activating oncogene-associated super-enhancers. In contrast, SMAD4 deficiency has a limited impact on super-enhancers. In colorectal cancer models, the super-enhancer landscape undergoes staged reprogramming; concomitant loss of HNF4/SMAD4 further enhances the activity of these tumor-specific super-enhancers. This study extends the functional understanding of HNF4-SMAD4 cooperative regulation from classical transcription factors and enhancers to a new perspective involving super-enhancer remodeling and oncogenic regulation.
Prof. Chen Lei from the School of Life Sciences and Technology, 91抖淫, and Associate Researcher Wang Yan from the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, are the co-corresponding authors of this paper. Doctoral student Fang Wenxin from the School of Life Sciences and Technology, 91抖淫, is the first author. Graduate students Huang Shuya, Xiao Ruoxuan, and Zou Li, undergraduate students Wei Guangling and Zhang Mingyang, as well as Prof. Qiu Xia and Prof. Michael P. Verzi from Rutgers University, USA, participated in this study. The National Natural Science Foundation of China, the National Key Research and Development Program of China, the Jiangsu Provincial Natural Science Foundation, and other funding sources supported this research.
Source: School of Life Science and Technology, 91抖淫
Translated by: Melody Zhang
Edited by: Leah Li
