Eskiocak, Onur, Subhash, Santhilal, Shah, Vyom, Moresco, Phill, Beyaz, Semir (May 2024) Divergent coactivator usage and CREB1 activity controls tuft lineage commitment. In: UNSPECIFIED.
Abstract
The precise coordination of co-activators and transcription factors in shaping distinct intestinal epithelial cell types during intestinal stem cell (ISC) differentiation, especially the roles of CBP and P300, remains poorly understood despite extensive gene regulation studies. Here using conditional and inducible genetic models, we identify P300 but not CBP as a specific repressor of tuft and goblet lineages. Both ISC- and IEC-specific deletion of P300 elicited selective expansion of tuft and goblet cells with upregulation of gene modules that orchestrate their differentiation without affecting Paneth and enteroendocrine linages. Intestinal organoids that lack P300 more robustly upregulated tuft cell marker genes in response to IL13, a cytokine that drives type-II immunity and tuft cell expansion. Because P300 often acts as co-activator of TFs that regulate lineage specific gene expression, we hypothesized that lack of P300 repressed a repressor of tuft cell lineage. Among TFs that associate with P300, we tested whether CREB1 regulates P300 mediated restriction of tuft lineage. Surprisingly, we found that CREB1 is necessary for tuft cell commitment in vivo and expansion in response to IL13 treatment in organoids. Overall, these results contribute to our understanding of the complex regulatory mechanisms underlying the ISC differentiation to form specialized cell types in the intestinal epithelium.
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