The polycomb group protein L3MBTL1 represses a SMAD5-mediated hematopoietic transcriptional program in human pluripotent stem cells.
Bottom Line: Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells.We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell populations, thereby affecting erythroid differentiation.Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia.
Affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: email@example.com.Show MeSH
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Mentions: We, and others, have suggested that L3MBTL1 plays an important role in erythroid differentiation of human CD34+ HSPCs (Aziz et al., 2013; Perna et al., 2010). We found that downregulation of L3MBTL1 occurs during normal erythroid differentiation, in a manner similar to that seen during mesodermal differentiation (Figure 1A). We first assessed the effect of L3MBTL1-KD in iPSC-derived CD34+ cells undergoing erythroid differentiation, and observed a marked acceleration in the expression of the erythroid-specific marker GlyA (after 2 days in EPO-induced culture) by flow cytometry in the L3MBTL1-KD cells (Figure 4A). This was followed by a significant increase in the expression of several erythroid-specific transcription factors, especially EKLF (Figure 4B). We also confirmed this phenotype in β-thalassemic iPSCs (Papapetrou et al., 2011), which we lentivirally infected to express shRNAs targeting L3MBTL1 (Figure S4A). Similar to the CB-iPSC line, knocking down L3MBTL1 in thalassemic erythroid progeny also increased EKLF expression (Figure S4B) and increased fetal globin gene expression compared to controls (Figure S4C).
Affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: firstname.lastname@example.org.