A Feedback Loop Consisting of MicroRNA 23a/27a and the β-Like Globin Suppressors KLF3 and SP1 Regulates Globin Gene Expression

Abstract

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 targeting of the transcription factors KLF3 and SP1. Intriguingly, miR-23a and miR-27a further enhance the transcription of β-like globin genes through repression of KLF3 and SP1 binding to the β-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 β-like globin genes and the miR-23a∼27a∼24-2 cluster during erythropoiesis.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00623-13.

ACKNOWLEDGMENTS

We thank Bin Zhu from Peking Union Hospital for his assistance with the umbilical cord blood preparation.

This work was supported by grants from the National Natural Science Foundation of China (31040021 to J.Y.; 31201103 to Y.-N.M.; 31200977 to F.W.), the National Key Basic Research Program of China (2011CBA01100 to J.Y.), the IBMS, CAMS (2009RC03 to J.Y.; 2010PYB06 to J.Y.), the Beijing Municipal Science & Technology Commission (2010B071 to J.Y.), and the National Basic Research Program of China (2010CB530406 to J.-W.Z.)

Y.M., B.W., F.J., and D.W. performed the experimental design and analysis. H.L., Y.Y., H.D., and B.G. performed the luciferase reporter assays and the Western blot analysis. F.W., Y.Z., H.Y., and Z.Z. were responsible for the animal experiments. L.D. was responsible for the bioinformatics analysis. J.Y. and Y.M. designed the study and wrote the paper.

We declare no competing financial interests.