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. 2025 Feb 3;60(3):352-363.e6.
doi: 10.1016/j.devcel.2024.10.021. Epub 2024 Nov 22.

Frizzled5 controls murine intestinal epithelial cell plasticity through organization of chromatin accessibility

Lu Deng  1 , Xi C He  1 , Shiyuan Chen  1 , Ning Zhang  1 , Fengyan Deng  1 , Allison Scott  1 , Yanfeng He  2 , Dai Tsuchiya  1 , Sarah E Smith  1 , Michael Epp  1 , Seth Malloy  1 , Fang Liu  1 , Mark Hembree  1 , Qinghui Mu  3 , Jeffrey S Haug  1 , Ermanno Malagola  4 , Huzaifa Hassan  1 , Kaitlyn Petentler  1 , Rhonda Egidy  1 , Lucinda Maddera  1 , Jonathon Russell  1 , Yan Wang  1 , Hua Li  1 , Chongbei Zhao  1 , Anoja Perera  1 , Timothy C Wang  4 , Calvin J Kuo  3 , Linheng Li  5
Affiliations

Frizzled5 controls murine intestinal epithelial cell plasticity through organization of chromatin accessibility

Lu Deng et al. Dev Cell. .

Abstract

The homeostasis of the intestinal epithelium relies on intricate yet insufficiently understood mechanisms of intestinal epithelial plasticity. Here, we elucidate the pivotal role of Frizzled5 (Fzd5), a Wnt pathway receptor, as a determinant of murine intestinal epithelial cell fate. Deletion of Fzd5 in Lgr5+ intestinal stem cells (ISCs) impairs their self-renewal, whereas its deletion in Krt19+ cells disrupts lineage generation, without affecting crypt integrity in either case. However, a broader deletion of Fzd5 across the epithelium leads to substantial crypt deterioration. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) identifies that Fzd5 governs chromatin accessibility, orchestrating the regulation of stem- and lineage-related gene expression mainly in ISCs and progenitor cells. In summary, our findings provide insights into the regulatory role of Fzd5 in governing intestinal epithelial plasticity.

Keywords: Fzd5; Wnt pathway; chromatin accessibility; intestinal stem cell; plasticity; single-cell transcriptome and epigenome.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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