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Downregulation of ZBTB24 hampers the G0/1- to S-phase cell-cycle transition via upregulating the expression of IRF-4 in human B cells

Abstract

It has been recently identified that loss-of-function mutations in the uncharacterized gene ZBTB24 (zinc finger and BTB domain-containing 24) cause ICF2 (immunodeficiency, centromeric instability and facial anomalies syndrome 2) with immunological characteristics of greatly reduced serum antibodies and circulating memory B cells. ZBTB24 belongs to the large ZBTB family of transcriptional repressors with members like B-cell lymphoma 6 (BCL-6; ZBTB27) playing critical roles in B-cell functions. Given the genotype–phenotype correlation analyses in ICF2 patients and the high expression of ZBTB24 in human B cells, we, in the present study, investigated the function of ZBTB24 in human B-cell line Raji cells. Knockdown of endogenous ZBTB24 by small hairpin RNAs results in a significantly reduced proliferation through blocking the G0/1- to S-phase cell-cycle progression, but not apoptosis induction. Moreover, downregulation of ZBTB24 increases the expression of IRF-4 (interferon regulatory factor 4) and Blimp-1 (B lymphocyte-induced maturation protein 1), two crucial factors involved in the proliferation and differentiation of B cells. Importantly, ZBTB24 exerts these functions independent of BCL-6 as it does not affect the expression and function of BCL-6. Our study thus not only provides a molecular explanation for the B-cell and antibody defects observed in ZBTB24-deficient ICF2 patients, but also indicates that ZBTB24 represents a novel transcriptional factor essentially involved in human B-cell functions.

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Acknowledgements

We thank Dr Vivan J Bardwell from the University of Minnesota (USA) for the pGL3 vector containing 5xBCL6 binding sites and Dr Herbert C Morse III from the National Institutes of Health (USA) for the pcDNA4-BCOR-Myc vector. We thank Ms XueMei Zhu for her excellent technical assistance with FACS. This study was financially supported by the National Natural Science Foundation of China (31200672/31370871/81470564/31400768); Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); The Scientific Research Foundation for Returned Overseas Chinese Scholars from State Education Ministry to JW and YZ; Program for Cheung Kong Scholars and Innovative Research Team PCSIRT (IRT1075); Jiangsu Provincial Innovative Research Team; and Jiangsu Students’ Platform for Innovation and Entrepreneurship Training Program (201410285037).

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Liang, J., Yan, R., Chen, G. et al. Downregulation of ZBTB24 hampers the G0/1- to S-phase cell-cycle transition via upregulating the expression of IRF-4 in human B cells. Genes Immun 17, 276–282 (2016). https://doi.org/10.1038/gene.2016.18

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