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A feedback loop consisting of microRNA 23a/27a and the ?-like globin suppressors KLF3 and SP1 regulates globin gene expression.

ABSTRACT: The developmental stage-specific expression of the human ?-like globin genes has been studied for decades, and many transcriptional factors as well as other important cis elements have been identified. However, little is known about the microRNAs that potentially regulate ?-like globin gene expression directly or indirectly during erythropoiesis. In this study, we show that microRNA 23a (miR-23a) and miR-27a promote ?-like globin gene expression in K562 cells and primary erythroid cells through targeting of the transcription factors KLF3 and SP1. Intriguingly, miR-23a and miR-27a further enhance the transcription of ?-like globin genes through repression of KLF3 and SP1 binding to the ?-like globin gene locus during erythroid differentiation. Moreover, KLF3 can bind to the promoter of the miR-23a?27a?24-2 cluster and suppress this microRNA cluster expression. Hence, a positive feedback loop comprised of KLF3 and miR-23a promotes the expression of ?-like globin genes and the miR-23a?27a?24-2 cluster during erythropoiesis.

SUBMITTER: Ma Y

PROVIDER: S-EPMC3811682 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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A feedback loop consisting of microRNA 23a/27a and the β-like globin suppressors KLF3 and SP1 regulates globin gene expression.

Ma Yanni Y Wang Bin B Jiang Fengbing F Wang Dongsheng D Liu Huiwen H Yan Yunmeng Y Dong He H Wang Fang F Gong Bei B Zhu Yong Y Dong Lei L Yin Haixin H Zhang Zhongzu Z Zhao Hualu H Wu Zhikui Z Zhang Junwu J Zhou Jingguo J Yu Jia J

Molecular and cellular biology 20130805 20

The developmental stage-specific expression of the human β-like globin genes has been studied for decades, and many transcriptional factors as well as other important cis elements have been identified. However, little is known about the microRNAs that potentially regulate β-like globin gene expression directly or indirectly during erythropoiesis. In this study, we show that microRNA 23a (miR-23a) and miR-27a promote β-like globin gene expression in K562 cells and primary erythroid cells through ...[more]

PMID: 23918807

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Project description:MicroRNA cluster mirn23a has previously been shown to promote myeloid development at the expense of lymphoid development in overexpression and knockout mouse models. This polarization is observed early in hematopoietic development, with an increase in common lymphoid progenitors (CLPs) and a decrease in all myeloid progenitor subsets in adult bone marrow. The pool size of multipotential progenitors (MPPs) is unchanged; however, in this report we observe by flow cytometry that polarized subsets of MPPs are changed in the absence of mirn23a. Additionally, in vitro culture of MPPs and sorted MPP transplants showed that these cells have decreased myeloid and increased lymphoid potential in vitro and in vivo. We investigated the mechanism by which mirn23a regulates hematopoietic differentiation and observed that mirn23a promotes myeloid development of hematopoietic progenitors through regulation of hematopoietic transcription factors and signaling pathways. Early transcription factors that direct the commitment of MPPs to CLPs (Ikzf1, Runx1, Satb1, Bach1 and Bach2) are increased in the absence of mirn23a miRNAs as well as factors that commit the CLP to the B cell lineage (FoxO1, Ebf1, and Pax5). Mirn23a appears to buffer transcription factor levels so that they do not stochastically reach a threshold level to direct differentiation. Intriguingly, mirn23a also inversely regulates the PI3 kinase (PI3K)/Akt and BMP/Smad signaling pathways. Pharmacological inhibitor studies, coupled with dominant active/dominant negative biochemical experiments, show that both signaling pathways are critical to mirn23a's regulation of hematopoietic differentiation. Lastly, consistent with mirn23a being a physiological inhibitor of B cell development, we observed that the essential B cell transcription factor EBF1 represses expression of mirn23a. In summary, our data demonstrates that mirn23a regulates a complex array of transcription and signaling pathways to modulate adult hematopoiesis.

Dataset Information

A feedback loop consisting of microRNA 23a/27a and the ?-like globin suppressors KLF3 and SP1 regulates globin gene expression.

Publications

A feedback loop consisting of microRNA 23a/27a and the β-like globin suppressors KLF3 and SP1 regulates globin gene expression.

Similar Datasets

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