Alternative titles; symbols
HGNC Approved Gene Symbol: ZBTB7B
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:155,001,750-155,018,523 (from NCBI)
ZFP67 is an early growth response gene that encodes a zinc finger-containing transcription factor that binds to the promoter regions of type I collagen genes (e.g., COL1A1; 120150) and has a role in development (Widom et al., 1997).
Galera et al. (1994) cloned mouse Zfp67, which they designated cKrox. The deduced 427-amino acid protein contains 3 C-terminal zinc fingers of the C2H2 type. Expression of Zfp67 was enriched in mouse skin, but was absent in bone.
Using mouse Zfp67 as probe, Widom et al. (1997) identified ZFP67 in a human skin fibroblast cDNA library, and they cloned the full-length cDNA by 3-prime RACE. The deduced 539-amino acid protein contains an additional 117 N-terminal amino acids compared with the mouse sequence. The human and mouse proteins share about 88% identity overall, and they are identical in the zinc fingers.
Gross (2014) mapped the ZBTB7B gene to chromosome 1q21.3 based on an alignment of the ZBTB7B sequence (GenBank AF007833) with the genomic sequence (GRCh38).
Galera et al. (1994) determined that mouse Zfp67 bound specifically to a guanine-rich cis-acting element present twice in the promoter region of the mouse Col1a1 gene, and Zfp67 activated transcription from the Col1a1 promoter.
Widom et al. (1997) determined that, similar to other early response genes, expression of ZFP67 mRNA was upregulated following treatment of serum-starved human foreskin and adult dermal fibroblasts with retinoic acid. Transient transfections indicated that ZFP67 repressed transcription from the COL1A1 promoter and reduced the level of COL1A1 and fibronectin (135600) mRNA. N-terminal mutation analysis identified a potential activation domain.
Using reporter assays and small interfering RNA-mediated knockdown experiments, Kimura et al. (2006) showed that ZFP67 enhanced CDCP1 (611735) transcription in the human hematopoietic cell line K562, but not in Jurkat cells. Chromatin immunoprecipitation studies showed that ZFP67 bound to the CCP1 promoter in K562 cells, but not in Jurkat cells. Kimura et al. (2006) found a correlation between methylation of CpG sequences in the promoter region of CDCP1 and CDCP1 expression. Demethylation of the CpG sequences in lymphocytes induced CDCP1 expression, and its expression was further increased with ZFP67 overexpression.
Mouse CD4+CD8+ double-positive thymocytes differentiate into CD4+ helper-lineage cells upon expression of the transcription factor Th-POK but commit to the CD8+ cytotoxic lineage in its absence. Setoguchi et al. (2008) reported the redirected differentiation of class I-restricted thymocytes into CD4+CD8- helper-like T cells upon loss of Runx transcription factor complexes. A Runx-binding sequence within the Th-POK locus acts as a transcriptional silencer that is essential for Th-POK repression and for development of CD8+ T cells. Thus, Th-POK expression and genetic programming for T helper cell development are actively inhibited by Runx-dependent silencer activity, allowing for cytotoxic T-cell differentiation.
Vacchio et al. (2019) found that Thpok was necessary to establish the T follicular helper (Tfh) cell transcriptome and was required in mature mouse Cd4-positive T cells for Tfh differentiation in a cell-intrinsic manner. Cell-intrinsic functions of Thpok in Cd-positive T cells were also required for germinal center formation and function. Thpok promoted Bcl6 (109565) expression by binding to a region in its first intron, leading to Tfh cell differentiation. Zbtb7b also promoted expression of other genes, including Maf (177075), which cooperated with Bcl6 to mediate Thpok function in Tfh cell differentiation.
Dave et al. (1998) described the HD (helper deficient) mouse, a novel mutant with a specific defect in the generation of CD4+ T cells. The HD phenotype segregates as a recessive trait. The mutation causes redirection of all class II-restricted thymocytes to the CD8 lineage. He et al. (2005) identified the HD locus as the zinc finger transcription factor Th-POK (ZBTB7B). They showed that expression of Th-POK in the thymus normally restricted the CD4 lineage, and that constitutive expression leads to redirection of class I-restricted thymocytes to the CD4 lineage. The HD mutation is an A-to-G transition at nucleotide 1165 resulting in an arg-to-gly substitution at amino acid 389. This arg-to-gly substitution occurs within the second of 4 zinc finger domains of Th-POK and affects a residue predicted to interact directly with DNA. He et al. (2005) concluded that Th-POK is a master regulator of lineage commitment.
By microarray analysis to compare mouse gene expression in preselection double-positive thymocytes with intrathymically T-cell receptor-signaled thymocytes, Sun et al. (2005) found that Zfp67 was selectively upregulated during positive selection of CD4-positive but not CD8-positive T cells. Forced expression of Zfp67 on major histocompatibility complex class I-restricted thymocytes deviated cells from CD8 to CD4 differentiation. Sun et al. (2005) concluded that ZFP67 is a chief CD4-differentiating factor during T-cell development.
Using an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, Kennedy et al. (2020) found that mice homozygous for an arg367-to-gln (R367Q) mutation in Zbtb7b were protected against neuroinflammation in experimental cerebral malaria caused by infection with Plasmodium berghei ANKA. Chromatin immunoprecipitation-sequencing analysis revealed that Zbtb7b bound to genes involved in ontogeny and activity of lymphoid cells, and molecular modeling predicted that the R367Q mutation affected the ability of Zbtb7b to bind DNA. R367Q mutant mice had a defect in thymic development and lacked Cd4-positive T cells, resulting in reduced production of proinflammatory cytokines and protection against lethal neuroinflammation. Reduced production of proinflammatory cytokines also increased the susceptibility of R367Q mutant mice to mycobacterial infection.
Dave, V. P., Allman, D., Keefe, R., Hardy, R. R., Kappes, D. J. HD mice: a novel mouse mutant with a specific defect in the generation of CD4(+) T cells. Proc. Nat. Acad. Sci. 95: 8187-8192, 1998. [PubMed: 9653162] [Full Text: https://doi.org/10.1073/pnas.95.14.8187]
Galera, P., Musso, M., Ducy, P., Karsenty, G. c-Krox, a transcriptional regulator of type I collagen gene expression, is preferentially expressed in skin. Proc. Nat. Acad. Sci. 91: 9372-9376, 1994. [PubMed: 7937772] [Full Text: https://doi.org/10.1073/pnas.91.20.9372]
Gross, M. B. Personal Communication. Baltimore, Md. 8/28/2014.
He, X., He, X., Dave, V. P., Zhang, Y., Hua, X., Nicolas, E., Xu, W., Roe, B. A., Kappes, D. J. The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433: 826-833, 2005. [PubMed: 15729333] [Full Text: https://doi.org/10.1038/nature03338]
Kennedy, J. M., Georges, A., Bassenden, A. V., Vidal, S. M., Berghuis, A. M., Taniuchi, I., Majewski, J., Lathrop, M., Behr, M. A., Langlais, D., Gros, P. ZBTB7B (ThPOK) is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis. Infect Immun. 88: e00845-19, 2020. Note: Electronic Article. [PubMed: 31792077] [Full Text: https://doi.org/10.1128/IAI.00845-19]
Kimura, H., Morii, E., Ikeda, J., Ezoe, S., Xu, J.-X., Nakamichi, N., Tomita, Y., Shibayama, H., Kanakura, Y., Aozasa, K. Role of DNA methylation for expression of novel stem cell marker CDCP1 in hematopoietic cells. Leukemia 20: 1551-1556, 2006. [PubMed: 16926850] [Full Text: https://doi.org/10.1038/sj.leu.2404312]
Setoguchi, R., Tachibana, M., Naoe, Y., Muroi, S., Akiyama, K., Tezuka, C., Okuda, T., Taniuchi, I. Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development. Science 319: 822-825, 2008. [PubMed: 18258917] [Full Text: https://doi.org/10.1126/science.1151844]
Sun, G., Liu, X., Mercado, P., Jenkinson, S. R., Kypriotou, M., Feigenbaum, L., Galera, P., Bosselut, R. The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nature Immun. 6: 373-381, 2005. [PubMed: 15750595] [Full Text: https://doi.org/10.1038/ni1183]
Vacchio, M. S., Ciucci, T., Gao, Y., Watanabe, M., Balmaceno-Criss, M., McGinty, M. T., Huang, A., Xiao, Q., McConkey, C., Zhao, Y., Shetty, J., Tran, B., Pepper, M., Vahedi, G., Jenkins, M. K., McGavern, D. B., Bosselut, R. A Thpok-directed transcriptional circuitry promotes Bcl6 and Maf expression to orchestrate T follicular helper differentiation. Immunity 51: 465-478, 2019. [PubMed: 31422869] [Full Text: https://doi.org/10.1016/j.immuni.2019.06.023]
Widom, R. L., Culic, I., Lee, J. Y., Korn, J. H. Cloning and characterization of hcKrox, a transcriptional regulator of extracellular matrix gene expression. Gene 198: 407-420, 1997. [PubMed: 9370309] [Full Text: https://doi.org/10.1016/s0378-1119(97)00360-0]