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Identification of Molecular Mechanisms Responsible for the MMP-9-1562C/T Dependent Differential Regulation of Matrix Metalloproteinase-9 Expression in Human Neurons
Pabian-Jewuła, S.; Ambrożek-Latecka, M.; Brągiel-Pieczonka, A.; Nowicka, K.; Rylski, M. Identification of Molecular Mechanisms Responsible for the MMP-9-1562C/T Dependent Differential Regulation of Matrix Metalloproteinase-9 Expression in Human Neuron-like Cells. Genes2023, 14, 2028.
Pabian-Jewuła, S.; Ambrożek-Latecka, M.; Brągiel-Pieczonka, A.; Nowicka, K.; Rylski, M. Identification of Molecular Mechanisms Responsible for the MMP-9-1562C/T Dependent Differential Regulation of Matrix Metalloproteinase-9 Expression in Human Neuron-like Cells. Genes 2023, 14, 2028.
Pabian-Jewuła, S.; Ambrożek-Latecka, M.; Brągiel-Pieczonka, A.; Nowicka, K.; Rylski, M. Identification of Molecular Mechanisms Responsible for the MMP-9-1562C/T Dependent Differential Regulation of Matrix Metalloproteinase-9 Expression in Human Neuron-like Cells. Genes2023, 14, 2028.
Pabian-Jewuła, S.; Ambrożek-Latecka, M.; Brągiel-Pieczonka, A.; Nowicka, K.; Rylski, M. Identification of Molecular Mechanisms Responsible for the MMP-9-1562C/T Dependent Differential Regulation of Matrix Metalloproteinase-9 Expression in Human Neuron-like Cells. Genes 2023, 14, 2028.
Abstract
The MMP-9-1562C/T polymorphism influence incidence and course of many diseases of the central nervous system. We found, using luciferase assays and Q-RT-PCR technique, allele-specific in-fluence of MMP-9-1562C/T polymorphism on the MMP-9 promoter activity and on the expression of MMP-9 mRNA in human neurons derived from SH-SY5Y cells. Then, we have elucidated the mechanism responsible for the allele-specific action of the MMP-9-1562C/T polymorphism on transcriptional regulation of the MMP-9 gene using pull-down assay combined with mass spec-trometry analysis, EMSA and EMSA supershift techniques, as well as DsiRNA-dependent gene silencing. We have found that MMP-9 promoter activity and MMP-9 mRNA expression are reg-ulated in human neurons in the MMP-9-1562C/T allele-specific manner with stronger upregulation conferred by the C allele. Moreover, we have revealed that the allele-specific action of the MMP-9-1562C/T polymorphism on the neuronal MMP-9 expression is related to HDAC1 and ZNF384 transcriptional regulators. We show that HDAC1 and ZNF384 bind differentially to the C and the T alleles forming in vitro different regulatory complexes. Moreover, our data demonstrate that HDAC1 and ZNF384 downregulate differentially the MMP-9 gene promoter activity and MMP-9 mRNA expression in vivo in human neurons acting mostly via the T allele.
Keywords
MMP-9; MMP-9-1562C/T polymorphism; transcriptional regulation; brain; human neurons
Subject
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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