Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion

•Gata1, Tal1, Lmo2, and c-Myc reprogram fibroblasts to erythroid progenitors (iEPs)•iEP gene expression is more similar to that of primitive than definitive erythroblasts•Klf1 or Myb overexpression induces adult hemoglobin expression in iEPs

SummaryErythroid cell commitment and differentiation proceed through activation of a lineage-restricted transcriptional network orchestrated by a group of well characterized genes. However, the minimal set of factors necessary for instructing red blood cell (RBC) development remains undefined. We employed a screen for transcription factors allowing direct lineage reprograming from fibroblasts to induced erythroid progenitors/precursors (iEPs). We show that Gata1, Tal1, Lmo2, and c-Myc (GTLM) can rapidly convert murine and human fibroblasts directly to iEPs. The transcriptional signature of murine iEPs resembled mainly that of primitive erythroid progenitors in the yolk sac, whereas addition of Klf1 or Myb to the GTLM cocktail resulted in iEPs with a more adult-type globin expression pattern. Our results demonstrate that direct lineage conversion is a suitable platform for defining and studying the core factors inducing the different waves of erythroid development.

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