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Identification of RUNX1 targets in iLSCs

ABSTRACT: We identified 2 phenotypically and functionally distinct populations in our AML-iPSC line upon hematopoietic differentiation. One population is phenotypically and functionally a leukemia stem cell population (iLSCs = Samples A) and the second is more differentiated (iBlasts = Samples S). We found RUNX1 to be critical for iLSC maintenance and used gene expression and chromatin accessibility analyses after RUNX1 KD in iLSCs and iBlasts to identify the molecular mechanism of RUNX1 in iLSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143471 | GEO | 2020/06/03

REPOSITORIES: GEO

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Project description:The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice were generated that lacked Runx1 expression in epithelial cells of the GI tract. These mice were crossed onto the ApcMin background, sacrificed, and their intestinal tumor phenotypes were compared with ApcMin Runx1 wildtype control mice. Apc-wildtype Runx1-mutant mice were also examined for tumor development. Colons from Runx1 knockout and wildtype mice were used for genome-wide mRNA expression analyses followed by gene-specific quantitative RT-PCR of whole colon and colon epithelium, to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in ApcMin mice. Notably, epithelial Runx1 deficiency in Apc-wildtype mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of metastatic phenotype and poor prognosis. Gene-specific analysis of Runx1 deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract. A total of 8 colon tissue RNA samples were analyzed, comprising 4 colon samples from wild-type mice (Villin-Cre negative / Runx1-floxed) and 4 colon samples from mice that lack epithelial expression of Runx1 (Villin-Cre positive/Runx1-floxed).

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Identification of RUNX1 targets in iLSCs

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