Genetic variation at a Yin-Yang 1 response site regulates the transcription of cyclin-dependent kinase inhibitor p18INK4C transcript in lupus-prone mice.
Genetic variation at a Yin-Yang 1 response site regulates the transcription of cyclin-dependent kinase inhibitor p18INK4C transcript in lupus-prone mice.
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DOI：
10.4049/jimmunol.1101992
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发表时间：
2012-05-15
期刊：
影响因子：
--
通讯作者：
Morel L
中科院分区：
文献类型：
--
作者：
Potula HH;Morel L
我们之前已经证明，在携带Sle 2c 1狼疮易感基因的小鼠的B细胞中，细胞周期蛋白依赖性激酶抑制剂p18基因启动子中的一个新的−74 C到T突变与p18表达降低相关。为了确定−74 C/T SNP的功能，我们对小鼠p18基因的近端启动子进行了表征。通过连续缺失对5'侧翼区进行功能分析，发现了−300和+1之间的关键元件，证实了计算机预测，即−74 T等位基因在两个等位基因共有的现有结合位点附近产生了一个新的YY-1结合位点。此外，我们发现YY-1，E2 F1和Sp-1可以协同增强p18启动子的活性。突变失活显示YY-1结合以等位基因依赖的方式调节p18活性。脾B细胞提取物的EMSA直接证明YY-1与p18启动子结合，C和T等位基因之间存在差异。我们还确定在体内染色质免疫沉淀，T等位基因导致增加YY-1和减少Nrf-2结合p18启动子相比，C等位基因在B细胞。因此，YY-1是p18基因表达的直接调节因子，其等位基因依赖性方式与通过增加YY-1结合诱导较低p18转录活性的狼疮相关T等位基因一致。这些结果确立了p18 −74 C/T突变是B1 a细胞扩增的主要致病变异体，这是NZB和NZM 2410狼疮易感菌株的特征。
We have previously shown that a novel −74 C to T mutation in the promoter of the cyclin-dependent kinase inhibitor p18 gene was associated with a reduced p18 expression in B cells from mice carrying the Sle2c1 lupus susceptibility locus. To determine the function of the −74 C/T SNP, we have characterized the proximal promoter of the mouse p18 gene. Functional analysis of the 5' flanking region by sequential deletions revealed crucial elements between −300 and +1, confirming the in silico prediction that the −74 T allele created a novel YY-1 binding site adjacent to an existing one common to both alleles. Moreover, we found that YY-1, E2F1 and Sp-1 can synergistically enhance the activity of the p18 promoter. Mutational inactivation revealed that YY-1 binding regulates the p18 activity in an allele-dependent fashion. EMSAs with splenic B cell extracts directly demonstrated that YY-1 binds to the p18 promoter with differences between the C and the T alleles. We also determined in vivo by chromatin immunoprecipitation that the T allele resulted in increased YY-1 and decreased Nrf-2 binding to the p18 promoter as compared to the C allele in B cells. Thus, YY-1 is a direct regulator of p18 gene expression in an allele-dependent fashion that is consistent with the lupus-associated T allele inducing a lower p18 transcriptional activity by increasing YY-1 binding. These results establish the p18 −74 C/T mutation as the leading causal variant for the B1a cell expansion that characterizes the NZB and NZM2410 lupus-prone strains.
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DOI：
10.4161/cc.7.23.7187
发表时间：
2008-12
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Forget A;Ayrault O;den Besten W;Kuo ML;Sherr CJ;Roussel MF
通讯作者：
Roussel MF
影响因子：
3.7
作者：
Pan X;Jones M;Jiang J;Zaprazna K;Yu D;Pear W;Maillard I;Atchison ML
通讯作者：
Atchison ML
影响因子：
64.5
作者：
COUREY, AJ;TJIAN, R
通讯作者：
TJIAN, R
影响因子：
2.6
作者：
Cordova, E. J.;Velazquez-Cruz, R.;Orozco, L.
通讯作者：
Orozco, L.
影响因子：
6
作者：
Ma, Qiang;Battelli, Lori;Hubbs, Ann F.
通讯作者：
Hubbs, Ann F.