Abstract
RNA-binding proteins (RBPs) integrate the processing of RNAs into post-transcriptional gene regulation, but the direct contribution of them to myeloid cell specification is poorly understood. Here, we report the first global RBP transcriptomic analysis of myeloid differentiation by combining RNA-seq analysis with myeloid induction in CD34+ hematopoietic progenitor cells. The downregulated expression of the KH-Type Splicing Regulatory Protein (KSRP) during monocytopoiesis and up-regulated expression during granulopoiesis suggests that KSRP has divergent roles during monocytic and granulocytic differentiation. A further comparative analysis of miRNA transcripts reveals that KSRP promotes the biogenesis of miR-129, and the expression patterns and roles of miR-129 in myeloid differentiation are equivalent to those of KSRP. Finally, miR-129 directly blocks the expression of Runt Related Transcription Factor 1 (RUNX1), which evokes transcriptional modulation by RUNX1. Based on our findings, KSRP, miR-129, and RUNX1 participate in a regulatory axis to control the outcome of myeloid differentiation.
Highlights
RNA-binding proteins (RBPs) integrate the processing of RNAs into post-transcriptional gene regulation, but the direct contribution of them to myeloid cell specification is poorly understood
Lineage-specifying transcription factors include PU.[1], which affects the hematopoiesis of multiple lineages in an early stage[3], and Gfi-1, C/EBPα and C/EBPε, which govern the differentiation of hematopoietic stem cells (HSCs) along the myeloid lineage toward granulocytes rather than monocytes[4,5]
Monocytic (M-) or granulocytic (G-) differentiation of CD34+ hematopoietic progenitor cells (HPCs) was induced by treating the cells with macrophage colonystimulating factor (M-CSF) or granulocyte colony-stimulating factor (G-CSF), respectively, for a 15-day period (Fig. 1a, left)[17]
Summary
RNA-binding proteins (RBPs) integrate the processing of RNAs into post-transcriptional gene regulation, but the direct contribution of them to myeloid cell specification is poorly understood. Lineage-specifying transcription factors include PU.[1], which affects the hematopoiesis of multiple lineages in an early stage[3], and Gfi-1, C/EBPα and C/EBPε, which govern the differentiation of hematopoietic stem cells (HSCs) along the myeloid lineage toward granulocytes rather than monocytes[4,5]. Epigenetic controls, such as histone modification and DNA methylation, are involved. MiR-129 acts downstream of KSRP to regulate myeloid differentiation and targets RUNX1 Based on these data, the KSRP−miR-129-RUNX1 regulatory axis promotes granulocyte differentiation at the expense of monocyte-macrophage differentiation, suggesting its role in orchestrating the ratio of these two phagocytes
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