| Summary: | Summary: Intestinal epithelial stem cell (IESC) fate is promoted by two major transcriptional regulators, the TCF4/β-catenin complex and ASCL2, which drive expression of IESC-specific factors, including Lgr5, Ephb2, and Rnf43. Canonical Wnt signaling via TCF4/β-catenin directly transactivates Ascl2, which in turn auto-regulates its own expression. Conversely, Let-7 microRNAs antagonize the IESC lineage by repressing specific mRNA targets. Here, we identify the zinc finger transcription factor PLAGL2 as a Let-7 target that regulates IESC fate. PLAGL2 drives an IESC expression signature, activates Wnt gene expression, and enhances a TCF/LEF reporter in intestinal organoids. In parallel, via cell-autonomous mechanisms, PLAGL2 is required for lineage clonal expansion and directly enhances expression of ASCL2. PLAGL2 also supports enteroid growth and survival in the context of Wnt ligand depletion. PLAGL2 expression is strongly associated with an IESC signature in colorectal cancer and may be responsible for contributing to the aberrant activation of an immature phenotype. : In this article, Madison and colleagues show that the zinc finger transcription factor PLAGL2 is a potent driver of intestinal stem cell lineage specification in organoids. This is mediated both via secreted signals, likely Wnts, activated by PLAGL2, and also by cell-autonomous and direct PLAGL2 activation of Ascl2, a transcription factor that drives stem cell fate. Keywords: Let-7, PLAGL2, ASCL2, intestinal epithelium, stem cell
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