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Tnfaip8 Regulates Intestinal Stemness and Terminal Differentiation of Secretory Progenitors
Author(s) -
Hood Ryan,
Chen Youhai,
Goldsmith Jason
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02598
Subject(s) - microbiology and biotechnology , wnt signaling pathway , biology , stem cell , pi3k/akt/mtor pathway , intestinal epithelium , progenitor cell , paneth cell , protein kinase b , lgr5 , goblet cell , cellular differentiation , small intestine , signal transduction , endocrinology , epithelium , biochemistry , genetics , gene
The intestine is a dynamic environment that relies on constant self‐renewal of the intestinal epithelium to maintain homeostasis. Maintenance of stem cell populations as well as coordinated cell fate determination is necessary for coordinating intestinal function and regeneration. Tumor necrosis factor‐alpha‐induced protein 8 (TIPE0) is a regulator of phosphoinositide 3‐kinase (PI3K)‐mediated signaling through the sequestration of membranous PIP2. The PI3K/protein kinase B (Akt)/‐catenin pathway regulates proliferation in the intestine in conjunction with Wnt signalling. We recently found that loss of Tipe0 leads to hyperactivation of microbiome‐mediated Akt/‐catenin signaling in the intestine and a single‐cell RNA sequencing survey of Tipe0‐/‐ small intestine found that Tipe0‐/‐ intestinal cells were shifted towards an undifferentiated state, with the notable exception of goblet cells, which were expanded.Here, we performed more in depth analysis of our existing sc‐RNASeq data set to better characterize the changes in intestinal differentiation seen with loss of TIPE0, using pseudo‐time based approaches. We hypothesized that various transcription factors/epigenetic regulators would be differentially expressed in the Tipe0‐/‐ intestine, underlying the expansion of goblet cells we had previously seen. In these studies, we confirmed that loss of Tipe0 causes a shift towards an undifferentiated state with an increase in Lgr5+ stem cells and transitional enterocytes and a consequent decrease in terminally differentiated enterocytes with the exception of goblet cells which were also enriched. Additionally, in this process we identified three possible novel regulators of terminal cell fate decisions in the intestinal secretory lineage: Nupr1, Kdm4a, and Gatad1. We propose that these novel regulators drive epigenetic changes involved in goblet cell (Nupr1) or tuft cell (Kdm4a and Gatad1) fate commitment and that TIPE0 may play a role in orchestrating terminal differentiation, likely through its regulation of homeostatic Akt/‐catenin signaling.