Functions Of ZBTB24 In Human Lymphocytes

Loss-of-function mutations in the uncharacterized gene ZBTB24 causes the Immunodeficiency, Centromeric Instability and Facial Anomalies syndrome 2(ICF2) with immunological characteristics of greatly reduced serum antibodies and circulating memory, but not total, B cells. ZBTB24 belongs to the large ZBTB family of transcriptional repressors with members like 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 studied the function of ZBTB24 in human B-cell lines. Knockdown of endogenous ZBTB24 by shRNAs results in a significantly reduced proliferation through blocking the G0/1 to S phase cell cycle progression, but not apoptosis-induction. Moreover, depletion of ZBTB24 increases the expression of IRF-4 and Blimp-1, both of which are capable of inducing the differntiation of B cells toward antbody-secreting cells at the expense of cellular growth. Preventing the upregulation of IRF-4 induced by ZBTB24-downregulation largely reverses the proliferation defects observed in ZBTB24-downregulated cells, indicating that ZBTB24 regulates the proliferation of B cells through IRF-4. Importantly, our data indicate that ZBTB24 exerts these functions independent of BCL-6 as it does not affect the expression and function of BCL-6. Interestingly, downregulation of ZBTB24 in the T-cell line Jurkat slightly inhibits the proliferations without affecting the level of IRF-4. These data suggest that ZBTB24 regulates the proliferation and/or differentiation of lymphocytes through different mechanisms. Our study thus not only provides a molecular explanation for the B-cell and antibody defects in ZBTB24-deficient ICF2 patients, but also indicates that ZBTB24 represents a novel transcriptional factor essentially involved in the function of B cells.