Downregulation of ZBTB24 hampers the G0/1- to S-phase cell-cycle transition via upregulating the expression of IRF-4 in human B cells.
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.
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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J
Liang
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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R
Yan
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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G
Chen
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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J
Feng
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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Wu
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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W
Ren
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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Zhu
Department of Pathophysiology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
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Y
Zhao
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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XM
Gao
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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0000-0002-4458-3741
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Wang
D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D007399:Interphase; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins; D000099218:Interferon Regulatory Factor-4; C560314:ZBTB24 protein, human; C087042:PRDM1 protein, human