School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, India; Department of Physiology, A.B.N. Seal College, Cooch Behar, West Bengal, India.
School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, India.
Comput Biol Med. 2022 Jun;145:105404. doi: 10.1016/j.compbiomed.2022.105404. Epub 2022 Mar 15.
Matrix metalloproteinase 3 (MMP3) plays a crucial role in cancer progression and development by proteolyzing extracellular matrix substrates. Primarily, the expression of MMP3 is regulated at the transcriptional level. The minute interplay of various transcription factor binding motifs at the promoter region is responsible for the altered expression of the genes. Single nucleotide polymorphism (SNP) at the transcription factor binding sites shows specific effects on gene expressions. Genome-wide association study (GWAS) strongly reported the association of common SNPs (rs3025058, rs522616, and rs617819) of MMP3 promoter with disease progression. The insufficient functional analysis of these promoter SNPs indicates the need for extensive mechanistic analysis on the effects of allelic variants upon transcription factor binding at MMP3 promoter.
The binding of transcription factors on the MMP3 promoter sequence was investigated by a virtual laboratory. The interaction between the specific transcription factor and promoter DNA with allelic variants was analyzed by computational tools.
It was found that transcription factor c-Myb and Smad4 binding on MMP3 promoter were altered due to the presence of rs522616 and rs617819 SNPs, respectively. Further, the binding affinity of Smad4 to the MMP3 promoter containing C allele at -375 region is higher than that of its allelic variant G.
This study presented that the complex of Smad4-DNA fragment containing C allele has higher binding affinity and stability as compared with its allelic variant. Hence, it is predicted that rs617819 polymorphism directly affects the Smad4 binding motif on MMP3 promoter and alters its gene expression.
基质金属蛋白酶 3（MMP3）通过蛋白水解细胞外基质底物在癌症进展和发展中发挥关键作用。主要地，MMP3 的表达受转录水平调控。启动子区域各种转录因子结合基序的微小相互作用负责基因表达的改变。转录因子结合位点的单核苷酸多态性（SNP）对基因表达具有特定影响。全基因组关联研究（GWAS）强烈报告了 MMP3 启动子常见 SNP（rs3025058、rs522616 和 rs617819）与疾病进展的关联。这些启动子 SNP 的功能分析不足表明需要对等位变异对 MMP3 启动子转录因子结合的影响进行广泛的机制分析。
通过虚拟实验室研究了转录因子在 MMP3 启动子序列上的结合。通过计算工具分析了特定转录因子与具有等位变异的启动子 DNA 之间的相互作用。
发现由于 rs522616 和 rs617819 SNP 的存在，转录因子 c-Myb 和 Smad4 对 MMP3 启动子的结合发生了改变。此外，在 -375 区域含有 C 等位基因的 MMP3 启动子中 Smad4 的结合亲和力高于其等位基因 G 的结合亲和力。
本研究表明，含有 C 等位基因的 Smad4-DNA 片段复合物具有更高的结合亲和力和稳定性，与其等位基因变体相比。因此，可以预测 rs617819 多态性直接影响 MMP3 启动子上的 Smad4 结合基序并改变其基因表达。
