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MicroRNAs as regulators and effectors of hematopoietic transcription factors

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Abstract Hematopoiesis is a highly‐regulated development process orchestrated by lineage‐specific transcription factors that direct the generation of all mature blood cells types, including red blood cells, megakaryocytes, granulocytes, monocytes, and lymphocytes. Under homeostatic conditions, the hematopoietic system of the typical adult generates over 1011 blood cells daily throughout life. In addition, hematopoiesis must be responsive to acute challenges due to blood loss or infection. MicroRNAs (miRs) cooperate with transcription factors to regulate all aspects of hematopoiesis, including stem cell maintenance, lineage selection, cell expansion, and terminal differentiation. Distinct miR expression patterns are associated with specific hematopoietic lineages and stages of differentiation and functional analyses have elucidated essential roles for miRs in regulating cell transitions, lineage selection, maturation, and function. MiRs function as downstream effectors of hematopoietic transcription factors and as upstream regulators to control transcription factor levels. Multiple miRs have been shown to play essential roles. Regulatory networks comprised of differentially expressed lineage‐specific miRs and hematopoietic transcription factors are involved in controlling the quiescence and self‐renewal of hematopoietic stem cells as well as proliferation and differentiation of lineage‐specific progenitor cells during erythropoiesis, myelopoiesis, and lymphopoiesis. This review focuses on hematopoietic miRs that function as upstream regulators of central hematopoietic transcription factors required for normal hematopoiesis. This article is categorized under: RNA in Disease and Development > RNA in Development Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
Schematic overview of the interplay of hematopoietic microRNAs (miRs) and transcription factor (TF). Hierarchical representation of hematopoiesis with hematopoietic stem cell (HSC) at the apex, generating increasingly restricted multipotent progenitors and downstream lineage‐specific cells. E, erythrocytes; G, granulocytes; M, monocytes/macrophages; MK, megakaryocytes. MiRs function as either regulators or effectors of key transcription factors during normal hematopoiesis. Repression of lineage‐specific TFs influences lineage selection, blocks differentiation, and supports expansion of cell populations. Declining levels of miRs targeting lineage‐specific TFs promotes differentiation. Conversely, repression of TFs required maintaining self‐renewal, multipotency or differentiation of alternate lineages promotes differentiation of specific hematopoietic cell types. MiRs and TFs that increase are depicted in red, whereas miRs and TFs that decline are depicted in black
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Schematic examples of hematopoietic transcription factor‐microRNAs (miR)‐mediated autoregulatory loop. (a) MYB activates transcription of miR‐15a. MiR‐15a directly targets MYB, creating a negative feedback loop to control MYB levels during erythropoiesis. (b) RUNX1 transcriptionally stimulates miR‐27a expression, which in turn directly targets RUNX1 during megakaryocytopoiesis. (c) During monocytopoiesis, RUNX1 transcriptionally represses miR‐17‐5p, miR‐20a, and miR‐106a, each of which directly targets RUNX1. Reduced miR‐17/20a/106a levels therefore further enhance RUNX1 levels and monocytopoiesis. (d) Increasing EGR2 levels repress miR‐142‐3p transcription during monocytopoiesis, leading to increased EGR2 levels following loss of miR‐142‐3p‐mediated inhibition of EGR2 expression
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Development

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