TNFAIP8 Regulates Intestinal Epithelial Cell Differentiation and May Alter Terminal Differentiation of Secretory Progenitors

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.