IMP1 is a novel Post-Transcriptional Regulator of Early Erythroid Development and Embryonic Globin output

The RNA-binding protein IMP1 is a developmentally expressed, post-transcriptional regulator involved in mRNA stability and translation. In the erythroid lineage, IMP1 was found expressed in fetal, but repressed in adult erythroid cells, being amongst 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, TMT-based proteomics revealed significant changes in the proteome, correlating with differential abundance of proteins in fetal compared to adult erythroid cells, indicating role in specification of the fetal erythroid phenotype. Notwithstanding, there was no significant effect of IMP1 knockdown or knockout in HUDEP-1 on fetal g-globin levels. However, there was a marked, significant reduction in embryonic z- and e-globin protein levels, which along with strong association of IMP1 with their transcripts, supports direct post-transcriptional regulation by IMP1. Furthermore, IMP1 was found to be significantly more abundant in human iPSC-embryonic erythroid cell surrogates than even fetal erythroid cells, suggesting a potentially more predominant role at this earlier, poorly characterised stage of erythroid development. The study uncovers novel role for IMP1, reveals 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 haemoglobinopathies, targeting the mechanisms by which IMP1 enhances embryonic globin translation could complement transcriptional strategies, enabling therapeutic levels to be achieved.