DGCR14 Induces Il17a Gene Expression through the RORγ/BAZ1B/RSKS2 Complex

Abstract

The Dgcr14/Es2 gene is located in a chromosomal region the loss of which has been associated with DiGeorge syndrome, a cause of immunodeficiency, heart defects, and skeletal abnormalities. However, the role of DGCR14 protein remains to be elucidated. Here, I found that DGCR14 protein acts as a coactivator of RORγt in T_H17 cells. Biochemical purification of the RORγ coregulator complex allowed me to identify the associated DGCR14 protein by matrix-assisted laser desorption ionization–time of flight mass spectrometry. Overexpression of Dgcr14 mRNA enhanced RORγt-mediated transcriptional activity and facilitated T_H17 cell differentiation. Furthermore, knockdown of Dgcr14 reduced Il17a mRNA expression. I also found that DGCR14 associated with ribosomal S6 kinase 2 (RSK2, also called RpS6ka3) and BAZ1B, both of which were recruited to the Il17a promoter during T_H17 cell differentiation. Knockdown of Baz1b or RpS6ka3 also reduced Il17a mRNA expression, and Baz1b knockdown increased transcriptional suppressive histone marks (histone H3K9me3) on the Il17a promoter. My findings showed the roles of DGCR14, RSK2, and BAZ1B in the transcriptional regulation of Il17a mRNA during T_H17 cell differentiation.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00926-14.

ACKNOWLEDGMENTS

I thank A. Yoshimura, M. Makishima, and S. Nakagawa for critical discussions. I particularly thank A. Yoshimura, who assisted me in this project. I also thank Y. Yogiashi, R. Tanikawa, and S. Fujiyama-Nakamura for helping with protein purification and proteomics. I thank R. Nakagawa, T. Shichita, and all laboratory members for useful discussions.

This work was supported by a grant-in-aid for Basic Research on Priority Areas (Dynamics of Extracellular Environments and Immunological Self), a grant-in-aid for Young Scientists (B; 23791662), a grant-in-aid for Scientific Research (C; 25462382), the Cell Science Research Foundation, the Kanae Foundation for the Promotion of Medical Science, and the Mochida Memorial Foundation.