Abstract
The intestine is a highly proliferative dynamic environment that relies on constant self-renewal of the intestinal epithelium to maintain homeostasis. Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8 or TIPE0) is a regulator of PI3K-mediated signaling. By binding to PIP2 and PIP3, TIPE family members locally activate PI3K activity while globally inhibiting PI3K activity through sequestration of membranous PIP2. Single-cell RNA sequencing survey of Tipe0−/− small intestine was used to investigate the role of TIPE0 in intestinal differentiation. Tipe0−/− intestinal cells were shown to shift towards an undifferentiated state, with the notable exception of goblet cells. Additionally, three possible novel regulators of terminal cell fate decisions in the secretory lineage were identified: Nupr1, Kdm4a, and Gatad1. We propose that these novel regulators drive 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.
Highlights
Intestinal homeostasis relies on rapid and continuous self-renewal of the intestinal epithelium controlled by various inputs and signaling pathways
Terminal differentiation in the secretory lineage involves a number of different factors, including neurogenin 3 (Neurog3) in enteroendocrine cells [6,7,8], Kruppel-like factor 4 (Klf4) and sterile alpha motif pointed domain containing ETS transcription factor (Spdef) in goblet cells [9,10,11], growth factor independent 1 (Gfi1) in Paneth cells [12], and Gfi1b in tuft cells [13]
Given that TIPE0 modulates PI3K/Akt signaling and that expression of stem cell markers and beta-catenin targets are altered by loss of TIPE0, we investigated which genes may be responsible for the changes in the composition of the Tipe0−/− intestine
Summary
Intestinal homeostasis relies on rapid and continuous self-renewal of the intestinal epithelium controlled by various inputs and signaling pathways. The Wnt/β-catenin pathway is involved in determining the secretory lineage in the absence of Notch signaling [2]. Terminal differentiation in the secretory lineage involves a number of different factors, including neurogenin 3 (Neurog3) in enteroendocrine cells [6,7,8], Kruppel-like factor 4. Global increase in PI (3–5) P3 elevated PI3K/Akt signaling in Tipe0−/− intestinal epithelium, suggesting that TIPE0 may globally suppress. Aberrant PI3K/Akt signaling in the Tipe0−/− intestine was found to alter the cellular composition of the intestinal epithelium, causing a shift towards an undifferentiated state [22]. We use this phenomenon of altered differentiation in the Tipe0−/− gut, coupled to single-cell RNA-Seq pseudotime analyses, to discover novel regulators of secretory lineage fate commitment
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