The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells.
The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells.
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DOI：
10.1093/nar/gku1225
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发表时间：
2014-12-16
影响因子：
14.9
通讯作者：
Heikkinen S
中科院分区：
文献类型：
--
作者：
Norton L;Chen X;Fourcaudot M;Acharya NK;DeFronzo RA;Heikkinen S
在肝脏中，Wnt信号传导有助于肝细胞的代谢命运，但TCF 7 L2在此过程中的确切作用尚不清楚。我们采用时间RNA-Seq方法检测大鼠肝癌细胞中Tcf 7 l2沉默后3-96 h的基因表达，并将其与ChIP-Seq相结合，以研究TCF 7 L2对靶基因的调控机制。沉默Tcf 7 l2导致406个差异表达基因（DEG）的时间依赖性出现，包括细胞生长和分化的关键调节因子，以及氨基酸，脂质和葡萄糖代谢。近端TCF 7 L2结合强烈（峰值接近评分> 10）和早期mRNA表达变化（≤18 h）提示149个DEG的直接调节。TCF 7 L2的间接基因调节可能通过替代转录因子发生，包括Hnf 4a，Foxo 1，Cited 2，Myc和Lef 1，这些转录因子在Tcf 7 L2敲低后差异表达。Tcf 7 l2沉默增强了HNF 4 α的表达和染色质占有率，co-siRNA实验表明，HNF 4 α是TCF 7 L2调节代谢基因亚组所必需的，特别是那些参与脂质和氨基酸代谢的基因。我们的研究结果表明TCF 7 L2是肝脏表型的重要调节因子，并强调了TCF 7 L2基因调控的新机制，涉及多种肝脏转录途径之间的相互作用。
In the liver Wnt-signaling contributes to the metabolic fate of hepatocytes, but the precise role of the TCF7L2 in this process is unknown. We employed a temporal RNA-Seq approach to examine gene expression 3–96 h following Tcf7l2 silencing in rat hepatoma cells, and combined this with ChIP-Seq to investigate mechanisms of target gene regulation by TCF7L2. Silencing Tcf7l2 led to a time-dependent appearance of 406 differentially expressed genes (DEGs), including key regulators of cellular growth and differentiation, and amino acid, lipid and glucose metabolism. Direct regulation of 149 DEGs was suggested by strong proximal TCF7L2 binding (peak proximity score > 10) and early mRNA expression changes (≤18 h). Indirect gene regulation by TCF7L2 likely occurred via alternate transcription factors, including Hnf4a, Foxo1, Cited2, Myc and Lef1, which were differentially expressed following Tcf7l2 knock-down. Tcf7l2-silencing enhanced the expression and chromatin occupancy of HNF4α, and co-siRNA experiments revealed that HNF4α was required for the regulation of a subset of metabolic genes by TCF7L2, particularly those involved in lipid and amino-acid metabolism. Our findings suggest TCF7L2 is an important regulator of the hepatic phenotype, and highlight novel mechanisms of gene regulation by TCF7L2 that involve interplay between multiple hepatic transcriptional pathways.
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DOI：
10.1152/ajpendo.00249.2012
发表时间：
2012-11-01
影响因子：
5.1
作者：
Ip, Wilfred;Shao, Weijuan;Jin, Tianru
通讯作者：
Jin, Tianru
影响因子：
12.3
作者：
Frietze S;Wang R;Yao L;Tak YG;Ye Z;Gaddis M;Witt H;Farnham PJ;Jin VX
通讯作者：
Jin VX
影响因子：
3.5
作者：
Hectors, Tine L. M.;Vanparys, Caroline;Blust, Ronny
通讯作者：
Blust, Ronny
影响因子：
4.8
作者：
Inoue, Y;Hayhurst, GP;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK