SON Protein Regulates GATA-2 through Transcriptional Control of the MicroRNA 23a∼27a∼24-2 Cluster

• Published in: The Journal of biological chemistry Vol. 288; no. 8; pp. 5381 - 5388
• Main Authors: Ahn, Erin Eun-Young, Higashi, Tsunehito, Yan, Ming, Matsuura, Shinobu, Hickey, Christopher J., Lo, Miao-Chia, Shia, Wei-Jong, DeKelver, Russell C., Zhang, Dong-Er
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.02.2013; American Society for Biochemistry and Molecular Biology
• Subjects: 3' Untranslated Regions; Animals; Blood; Cell Differentiation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; GATA-2; GATA2 Transcription Factor - metabolism; Gene Expression Regulation; Gene Regulation; Hematopoiesis; Humans; K562 Cells; Leukemia, Myeloid, Acute - metabolism; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs - metabolism; Minor Histocompatibility Antigens; miR-23a∼27a∼24-2 Cluster; Models, Biological; Promoter Regions, Genetic; RNA Splicing; RNA, Messenger - metabolism; SON; Transcription Repressor; U937 Cells; Up-Regulation; RNA Splicing; MicroRNA; SON; Hematopoiesis; miR-23a∼27a∼24-2 Cluster; Transcription Repressor; Blood; GATA-2
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.447227

SON is a DNA- and RNA-binding protein localized in nuclear speckles. Although its function in RNA splicing for effective cell cycle progression and genome stability was recently unveiled, other mechanisms of SON functions remain unexplored. Here, we report that SON regulates GATA-2, a key transcription factor involved in hematopoietic stem cell maintenance and differentiation. SON is highly expressed in undifferentiated hematopoietic stem/progenitor cells and leukemic blasts. SON knockdown leads to significant depletion of GATA-2 protein with marginal down-regulation of GATA-2 mRNA. We show that miR-27a is up-regulated upon SON knockdown and targets the 3′-UTR of GATA-2 mRNA in hematopoietic cells. Up-regulation of miR-27a was due to activation of the promoter of the miR-23a∼27a∼24-2 cluster, suggesting that SON suppresses this promoter to lower the microRNAs from this cluster. Our data revealed a previously unidentified role of SON in microRNA production via regulating the transcription process, thereby modulating GATA-2 at the protein level during hematopoietic differentiation.