IMP1 is a novel posttranscriptional regulator of early erythroid development and embryonic globin output

The RNA-binding protein IMP1 is a developmentally expressed, posttranscriptional regulator involved in mRNA stability and translation. In the erythroid lineage, IMP1 was found to be expressed in fetal but repressed in adult erythroid cells, being among the most differentially expressed proteins between these developmental stages, with levels decreasing sequentially as erythroid ontogeny progresses. To investigate its role in early erythroid cells, IMP1 was knocked down in the fetal erythroid line HUDEP-1. Knockdown did not alter expansion or differentiation. However, tandem mass tag-based proteomics revealed significant changes in the proteome, correlating with differential abundance of proteins in fetal compared with adult erythroid cells, indicating a role in specification of the fetal erythroid phenotype. Notwithstanding, there was no significant effect of IMP1 knockdown or knockout in HUDEP-1 on fetal γ-globin levels. However, there was a marked, significant reduction in embryonic ζ- and ε-globin protein levels, which, along with a strong association of IMP1 with their transcripts, supports direct posttranscriptional regulation by IMP1. Furthermore, IMP1 was found to be significantly more abundant in human induced pluripotent stem cells (iPSC)-embryonic erythroid cell surrogates than even fetal erythroid cells, suggesting a potentially more predominant role at this earlier, poorly characterized stage of erythroid development. This study uncovers a novel role for IMP1, reveals a previously unrecognized regulatory mechanism in early erythroid cells, and highlights the significant contribution of epitranscriptomic regulation in embryonic globin expression. As reactivation of embryonic globins in definitive erythroid cells holds therapeutic promise for hemoglobinopathies, targeting the mechanisms by which IMP1 enhances embryonic globin translation could complement transcriptional strategies, enabling therapeutic levels to be achieved.