A Negative Feedback Loop and Transcription Factor Cooperation Regulate Zonal Gene Induction by 2, 3, 7, 8-Tetrachlorodibenzo-p-Dioxin in the Mouse Liver.
A Negative Feedback Loop and Transcription Factor Cooperation Regulate Zonal Gene Induction by 2, 3, 7, 8-Tetrachlorodibenzo-p-Dioxin in the Mouse Liver.
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DOI：
10.1002/hep4.1848
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发表时间：
2022-04
影响因子：
5.1
通讯作者：
Bhattacharya S
中科院分区：
文献类型：
--
作者：
Yang Y;Filipovic D;Bhattacharya S
有效的环境有毒物有毒物质2、3、7、8-四氯二苯甲酸二氧化碳（TCDD）在小鼠肝脏中强烈诱导了细胞色素P450（CYP）蛋白CYP1A1和CYP1A2。 TCDD，即使在没有化学扰动的情况下，都会逐渐诱导泛滥。代谢功能和相关的基因基本上是沿着中央到门轴的肝脏中的划分，以研究TCDD的空间限制基因的机械基础，我们已经开发了单个单个模型的量级型号的模型。 iochemical信号传导然后将CYP1A1和CYP1A2诱导的途径纳入模型中的每个肝细胞中内源性Wnt调节代谢在我们的模型中，许多基因的分区不是区域的诱因：在这项工作中，我们使用数据驱动的计算模型来识别由潜在的基因表达的机械基础为我们的广泛贡献了解沿肝小叶的空间基因调节。
开发了多尺度的肝叶模型，以分析TCDD的细胞色素蛋白P450的纬向诱导机制。
The cytochrome P450 (Cyp) proteins Cyp1A1 and Cyp1A2 are strongly induced in the mouse liver by the potent environmental toxicant 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD), acting through the aryl hydrocarbon receptor (AHR). The induction of Cyp1A1 is localized within the centrilobular regions of the mouse liver at low doses of TCDD, progressing to pan‐lobular induction at higher doses. Even without chemical perturbation, metabolic functions and associated genes are basally zonated in the liver lobule along the central‐to‐portal axis. To investigate the mechanistic basis of spatially restricted gene induction by TCDD, we have developed a multiscale computational model of the mouse liver lobule with single‐cell resolution. The spatial location of individual hepatocytes in the model was calibrated from previously published high‐resolution images. A systems biology model of the network of biochemical signaling pathways underlying Cyp1A1 and Cyp1A2 induction was then incorporated into each hepatocyte in the model. Model simulations showed that a negative feedback loop formed by binding of the induced Cyp1A2 protein to TCDD, together with cooperative gene induction by the β‐catenin/AHR/TCDD transcription factor complex and β‐catenin, help produce the spatially localized induction pattern of Cyp1A1. Although endogenous WNT regulates the metabolic zonation of many genes, it was not a driver of zonal Cyp1A1 induction in our model. Conclusion: In this work, we used data‐driven computational modeling to identify the mechanistic basis of zonally restricted gene expression induced by the potent and persistent environmental pollutant TCDD. The multiscale model and derived results clarify the mechanisms of dose‐dependent hepatic gene induction responses to TCDD. Additionally, this work contributes to our broader understanding of spatial gene regulation along the liver lobule. A multiscale liver lobule model was developed to analyze the mechanisms of zonal induction of cytochrome proteins P450 by TCDD. We found that a negative feedback loop formed by TCDD‐CYP1A2 binding and cooperation between transcription factors play key roles in the zonal induction of cytochrome proteins.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
--
作者：
Gasior K;Hauck M;Wilson A;Bhattacharya S
通讯作者：
Bhattacharya S
影响因子：
3.8
作者：
Fader KA;Nault R;Kirby MP;Markous G;Matthews J;Zacharewski TR
通讯作者：
Zacharewski TR
影响因子：
4
作者：
Benary U;Kofahl B;Hecht A;Wolf J
通讯作者：
Wolf J
影响因子：
5.9
作者：
Dourson M;Becker RA;Haber LT;Pottenger LH;Bredfeldt T;Fenner-Crisp PA
通讯作者：
Fenner-Crisp PA