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The epithelial–mesenchymal transition (EMT) of lens epithelial cells enhanced their proliferation and migration and therefore induced the occurrence of posterior capsule opacity (PCO). Some studies revealed that Krüppel-like factor 1 (KLF1) promoted the proliferation and invasion of multiple types of cancer cells. Besides, the expression of KLF1 was elevated in the crystalline lens of cataract patients. However, the effect of KLF1 on the development of PCO remains unclear. In this study, TGF-β2 was used for the stimulation of human lens epithelial cell line to establish EMT (SRA01/04). The KLF1 was overexpressed and knocked down in SRA01/04 cells, the proliferation, migration and invasion of which were detected by clone formation assay, wound healing and transwell assay. In addition, ZBTB7A was overexpressed in KLF1-knocked down SRA01/04 cells, the proliferation and invasion of which were also measured by clone formation assay and transwell assay. KLF1 overexpression promoted the proliferation, migration and invasion of SRA01/04 cells. Moreover, KLF1 also promoted the expression of Vimentin, snail and α-SMA in SRA01/04 cells. KLF1 enhanced the expression of ZBTB7A and β-catenin, resulting in activation of ZBTB7A and Wnt/β-catenin signaling, while overexpression of ZBTB7A abolished the inhibitory effect of knocking down KLF1 on proliferation and invasion of SRA01/04 cells. These results indicated that KLF1 promoted the proliferation, migration and invasion of human lens epithelial cells by activating ZBTB7A and Wnt/β-catenin signaling pathway., GRAPHICAL ABSTRACT

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild. Fetal hemoglobin (HbF) fraction was elevated 2.2%–11.2% (reference value 6 months) in four of the five individuals for whom results were available. Ten of twelve individuals had undergone surgery at least once for lymphoid hypertrophy limited to the pharynx. In the most severely affected individual (individual 1), airway obstruction resulted in 17 surgical procedures before the age of 13 years. Sleep apnea was present in 8 of 10 individuals. In the nine unrelated individuals, ZBTB7A variants were novel and de novo. The six frameshift/nonsense and four missense variants were spread throughout the gene. This is the first report of a cohort of individuals with this novel syndromic neurodevelopmental disorder.

BackgroundDespite zinc finger and BTB domain-containing 7A (ZBTB7A) documented importance in multiple tumors, the function and clinical value in Colorectal cancer (CRC) remain elusive. The aim of this study was to evaluate the functional roles and the clinical value of ZBTB7A in CRC progression.MethodsThe level of ZBTB7A was detected in a large cohort of CRC patients (n = 189) by immunohistochemistry (IHC), and we analyzed the diagnostic and prognostic value of the protein. In addition, the functional roles of ZBTB7A on CRC were explored in vitro and in vivo.ResultsSurvival analyses indicated that patients with high ZBTB7A expression made the prognosis worse (P = 0.024). Functionally, knockdown of ZBTB7A could markedly inhibit tumor proliferation in vitro and in vivo, whereas ZBTB7A overexpression displayed the opposite results.ConclusionsZBTB7A was associated with poor survival outcomes and functioned as an oncogene in CRC patients, indicating that it is a potential prognostic biomarker and therapeutic target for CRC patients.

Backgroud ZBTB protein is an important member of the C2H2 zinc finger protein family. As a transcription factor, it is widely involved in the transcriptional regulation of genes, cell proliferation, differentiation, and apoptosis. The ZBTB7A has been largely linked to different kinds of tumors due to its diverse function. However, the value for ZBTB7A in uterine corpus endometrial carcinoma (UCEC) is unclear. Methods In our work, we assessed the importance of ZBTB7A in UCEC. Firstly, Using Oncomine and Tumor Immunoassay Resource (TIMER) databases to evaluate the expression of ZBTB7A. Secondly, we explored the co-expression network of ZBTB7A through the cBioPortal online tool, Metascape, and LinkedOmics. TIMER was also used to explore the relationship between ZBTB7A and tumor immune invasion, and to detect the correlation between the ZBTB7A and the marker genes related to immune infiltration. Finally, CCK8, migration, ChIP assays were introduced to partly validate ZBTB7A function in endometrial cancer cells. Results We found the ZBTB7A expression in TIMER was associated with various cancers, especially UCEC. The decreased expression of ZBTB7A was markedly related to the stage and prognosis of UCEC. Furthermore, ZBTB7A was also related to the expression of various immune markers such as Neutrophils, Dendritic cell, T cell (general), Th1, Th2, and Treg. Finally, we verified that ZBTB7A repressed E2F4 transcription and inhibited cells proliferation and migration. These results indicate that ZBTB7A may play a vital role in regulating immune cell infiltration in UCEC, and is a valuable prognostic marker. Conclusions In summary, we demonstrate that ZBTB7A is notably downregulated in UCEC, plays a vital role in regulating immune cell infiltration, possesses diagnostic and prognostic values and attenuates E2F4 transcription and cell proliferation, migration in vitro.

SUMMARY Elevated levels of fetal globin protect against β-hemoglobinopathies, such as sickle cell disease and β-thalassemia. Two zinc-finger (ZF) repressors, BCL11A and ZBTB7A/LRF, bind directly to the fetal globin promoter elements positioned at −115 and −200, respectively. Here, we describe X-ray structures of the ZBTB7A DNA-binding domain, consisting of four adjacent ZFs, in complex with the −200 sequence element, which contains two copies of four consecutive C:G base pairs. ZF1 and ZF2 recognize the 5′ C:G quadruple, and ZF4 contacts the 3′ C:G quadruple. Natural non-coding DNA mutations associated with hereditary persistence of fetal hemoglobin (HPFH) impair ZBTB7A DNA binding, with the most severe disruptions resulting from mutations in the base pairs recognized by ZF1 and ZF2. Our results firmly establish ZBTB7A/LRF as a key molecular regulator of fetal globin expression and inform genome-editing strategies that inhibit repressor binding and boost fetal globin expression to treat hemoglobinopathies., Graphical abstract, In brief Yang et al. show that the transcription factor ZBTB7A has features that deviate from conventional one finger-three bases recognition. Among the four fingers, ZF1 and ZF2 each contact two DNA bases. ZF3 does not make base-specific contacts but serves as a spacer to position ZF4 into the right location.

The present study aimed to determine the association between changes in Zbtb7a expression levels and heterogeneity of nasopharyngeal carcinoma (NPC) CNE3 sublines. CNE3 sublines were established by screening of serial dilution and continuous passage. Proliferative ability and tumorigenicity of the sublines were analyzed separately by soft-agar colony formation and mouse studies. The NPC tissues from mice were analyzed by histological evaluation and immunohistochemistry. The expression levels of Zbtb7a mRNA and protein were analyzed separately by quantitative reverse transcription polymerase chain reaction and western blotting. According to findings from the soft-agar colony formation and mouse studies, two sublines with increased tumorigenicity compared with other sublines were transfected transiently with Zbtb7a short hairpin RNA (shRNA) recombinant plasmid. The changes in viability, migration and invasion abilities were evaluated separately by MTT, colorimetric focus-formation, Transwell migration and invasion assays. The sublines CNE3-GX6 and CNE3-GX11 were selected for subsequent study due to increased tumorigenicity and increased Zbtb7a expression levels compared with the other sublines. High metastatic potency was not observed in all of the sublines. Zbtb7a expression levels were positively associated with tumorigenic degree of the sublines. The growth, migration and invasion abilities of the sublines transfected with Zbtb7a shRNA plasmid were decreased compared with the cells transfected with empty vector in the negative control group. The findings suggest Zbtb7a expression levels may be associated with heterogeneity of CNE3 sublines. Therefore, Zbtb7a may have an important role in the regulatory mechanism of NPC heterogeneity.

Background Patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) have a poor prognosis. Circular RNA circ_0016760 (circ_0016760) is associated with the development of NSCLC. At present, the role and regulatory mechanism of circ_0016760 in NSCLC have not been well explained. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was executed to detect the expression of circ_0016760, miR-577, and Zinc finger and BTB domain containing 7A (ZBTB7A) mRNA in NSCLC tissues and cells. The colony formation, migration, invasion, and extracellular acidification rate (ECAR) of NSCLC cells were determined through colony formation, transwell, or ECAR assays. The relationship between circ_0016760 or ZBTB7A and miR-577 was analyzed via dual-luciferase reporter and RNA pull-down or RNA immunoprecipitation (RIP) assays. Protein level of ZBTB7A was evaluated with Western blot analysis. Xenograft assay was conducted to confirm the role of circ_0016760 in vivo. Results Circ_0016760 and ZBTB7A were upregulated and miR-577 was downregulated in NSCLC tissues and cells. Circ_0016760 exhaustion curbed the colony formation, migration, invasion, and ECAR of NSCLC cells in vitro and impeded tumor growth in vivo. Mechanically, circ_0016760 modulated ZBTB7A expression via sponging miR-577 in NSCLC cells. MiR-577 downregulation abolished the repressive effects of circ_0016760 silencing on colony formation, migration, invasion, and ECAR of NSCLC cells. Also, ZBTB7A upregulation overturned the repressive impacts of miR-577 elevation on colony formation, migration, invasion, and ECAR of NSCLC cells. Conclusion Circ_0016760 silencing impeded NSCLC advancement through regulation of the miR-577/ZBTB7A axis.

Haemoglobin, the oxygen carrying protein in erythrocytes, is composed of two alpha- and two beta-like globin subunits. Its composition changes during gestation to meet varying oxygen demands of the developing embryo. A developmental switch occurs at birth, where foetal γ-globin expression is replaced by adult β-globin. Mutations in the γ-globin promoter can impair the switch and thereby cause elevated levels of foetal haemoglobin in adulthood, known as hereditary persistence of foetal haemoglobin (HPFH). This condition alleviates symptoms of adult β-globin disorders such as β-thalassemia and sickle cell disease. Reactivation of γ-globin expression currently offers a promising therapeutic approach for these diseases. A group of HPFH mutations clustered approximately 200 basepairs upstream of the γ-globin gene (-200 site) are believed to disrupt binding of transcriptional repressors of γ-globin expression. We have previously demonstrated that ZBTB7A, a transcriptional repressor highly expressed in erythroid cells and required for normal erythroid development, is able to bind this site in vitro, and binding is abolished by mutations in the -200 site. The purpose of this study was to further analyse the binding of ZBTB7A in vivo, as well as determine how it is regulated in erythroid cells. Here we use ChIP-Seq to demonstrate that ZBTB7A binds the γ-globin -200 site in cultured cells. Previous results suggested that Zbtb7a is regulated by the master regulator of erythropoiesis, KLF1, however, whether this effect was direct or mediated through other KLF1 target genes was unknown. We use a Klf1-/- mouse model, and the KLF1 inducible cell line, K1ER, to show that Zbtb7a is directly activated by KLF1. We also find that ZBTB7A has a novel transcription start site in both humans and mice that is highly expressed in erythroid cells and is induced upon erythroid cell differentiation. These findings suggest ZBTB7A plays a role in haemoglobin switching. As ZBTB7A is an important factor in erythroid maturation and survival, completely abolishing its expression may be detrimental. However, it may be possible to target the erythroid specific transcript to reduce ZBTB7A expression in erythroid cells alone, which may be sufficient to boost foetal haemoglobin as a potential therapeutic for β-haemoglobinopathies.