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: To investigate the mechanisms underlying the observed effects of L3MBTL1 on stem cell biology, we utilized an unbiased, genome-wide approach to analyze the gene expression profile (GEP) of two independent clones of undifferentiated L3MBTL1-KD iPSCs. We found increased expression of several BMP/SMAD target genes, as well as downregulation of negative regulators of BMP signaling (Figures 3A and 3B). ID2 and ID3 were among the upregulated genes, which are direct targets of BMP4 and regulate HSPC fate decisions (Hong et al., 2011; van Galen et al., 2014). HHEX also was upregulated; it is known to regulate globin gene expression during ontogeny and its promoter contains a 71 nucleotide BMP-responsive element (BRE) (Zhang et al., 2002). We also found increased expression of ZFP36L2, an RNA-binding protein required for BFU-E self-renewal (Zhang et al., 2013) (data not shown). Expression of SMAD7, which inhibits TGFβ-related signaling (Nakao et al., 1997), was downregulated, as were LEFTY1 and LEFTY2, which function as extracellular antagonists of Nodal signaling (Yeo and Whitman, 2001).
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.