期刊
GENES
卷 14, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/genes14112028
关键词
MMP-9; MMP-9-1562C/T polymorphism; transcriptional regulation; brain; human neurons
The MMP-9-1562C/T polymorphism has an impact on the occurrence and progression of disorders affecting the central nervous system. It specifically influences the MMP-9 promoter activity and mRNA expression in human neurons. This allele-specific effect is regulated by HDAC1 and ZNF384 transcriptional regulators.
The MMP-9-1562C/T polymorphism exerts an impact on the occurrence and progression of numerous disorders affecting the central nervous system. Using luciferase assays and Q-RT-PCR technique, we have discovered a distinct allele-specific influence of the MMP-9-1562C/T polymorphism on the MMP-9 (Extracellular Matrix Metalloproteinase-9) promoter activity and the expression of MMP-9 mRNA in human neurons derived from SH-SY5Y cells. Subsequently, by employing a pull-down assay paired with mass spectrometry analysis, EMSA (Electromobility Shift Assay), and EMSA supershift techniques, as well as DsiRNA-dependent gene silencing, we have elucidated the mechanism responsible for the allele-specific impact of the MMP-9-1562C/T polymorphism on the transcriptional regulation of the MMP-9 gene. We have discovered that the activity of the MMP-9 promoter and the expression of MMP-9 mRNA in human neurons are regulated in a manner that is specific to the MMP-9-1562C/T allele, with a stronger upregulation being attributed to the C allele. Furthermore, we have demonstrated that the allele-specific action of the MMP-9-1562C/T polymorphism on the neuronal MMP-9 expression is related to HDAC1 (Histone deacetylase 1) and ZNF384 (Zinc Finger Protein 384) transcriptional regulators. We show that HDAC1 and ZNF384 bind to the C and the T alleles differently, forming different regulatory complexes in vitro. Moreover, our data demonstrate that HDAC1 and ZNF384 downregulate MMP-9 gene promoter activity and mRNA expression in human neurons acting mostly via the T allele.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据