Cis-regulatory mechanisms governing stem and progenitor cell transitions

Abstract

Non-coding DNA elements differentially control stem and progenitor cell transitions required for development.

A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

“…Based on our findings that TGFβ has a direct effect on Gata2 through Smad4 ( Fig 4A) we observed direct binding of Smad4, to the -77kb upstream enhancer of the Gata2 gene 39,40 (Fig 4G), strengthening the observations from our gene expression analysis. We could also detect binding of Smad4 to a Smad7 intronic region (identified from our ChIP-Seq data) suggesting Smad7 as a direct target of TGFβ signaling in these cells (Fig 4G).…”

“…We verified these observations using qPCR of Gata2-bound chromatin in both Lhx2 and primary cells. The known -77kb Gata2 enhancer 39,40 as well as the Smad7 intronic region and the p57 promoter region identified from the ChIP-Seq were all enriched by GATA2 immunoprecipitation in Lhx2 cells (Fig 4C-D). Binding to the p57 promoter was further confirmed in a second multipotent cell line (Fig S1) -as well as in primary cells (Fig 4E-F) where the minimal amount of material needed for reliable ChIP-PCR results limited us to the use of LSK cells.…”

GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells

“…An inversion repositions a GATA-2-binding GATA2 cis element (−77 kb) (Grass et al, 2006) to a region upstream of the distant oncogene EVI1 , increasing EVI1 and decreasing GATA2 expression (Gröschel et al, 2014; Yamazaki et al, 2014). Deletion of the −77 kb site reduces Gata2 expression in myeloid progenitors, confers a differentiation blockade, and is embryonic lethal (Johnson et al, 2015). These results suggest that reduced GATA-2 expression in progenitors and ectopic EVI1 expression underlie leukemogenesis.…”

GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia

“…In hematopoiesis, two Gata2 cis -elements (Grass et al, 2003; Grass et al, 2006; Johnson et al, 2012; Johnson et al, 2015) induce expression of the master regulatory transcription factor GATA-2 (Tsai et al, 1994). A GATA-2-occupied Gata2 intronic enhancer (+9.5) containing an E-box-8 bp spacer-AGATAA composite element (E-box-GATA element) is required for hematopoietic stem cell (HSC) emergence from hemogenic endothelium in the mouse embryo (Gao et al, 2013).…”

“…A GATA-2-occupied Gata2 intronic enhancer (+9.5) containing an E-box-8 bp spacer-AGATAA composite element (E-box-GATA element) is required for hematopoietic stem cell (HSC) emergence from hemogenic endothelium in the mouse embryo (Gao et al, 2013). A GATA-2-occupied enhancer 77 kb upstream of Gata2 (-77), which contains several GATA motifs (Grass et al, 2006), confers myelo-erythroid progenitor differentiation potential, without impacting HSC emergence (Johnson et al, 2015). Insufficient GATA-2 levels/activity resulting from GATA2 coding or +9.5 enhancer mutations underlie hematologic diseases including primary immunodeficiencies that frequently progress to myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) (Dickinson et al, 2011; Hahn et al, 2011; Hsu et al, 2011; Ostergaard et al, 2011) and pediatric MDS/AML independent of immunodeficiency (Wlodarski et al, 2016).…”