Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3.
Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3.
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DOI：
10.1186/gb-2012-13-9-r52
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发表时间：
2012-09-26
期刊：
影响因子：
12.3
通讯作者：
Jin VX
中科院分区：
文献类型：
--
作者：
Frietze S;Wang R;Yao L;Tak YG;Ye Z;Gaddis M;Witt H;Farnham PJ;Jin VX
TCF7L2 转录因子与多种人类疾病有关，包括 2 型糖尿病和癌症。 TCF7L2 影响多种疾病相关基因表达的一种机制是与不同组织中的不同调控区域结合。为了验证这一假设，我们在 6 种人类细胞系中对 TCF7L2 进行了 ChIP-seq。我们鉴定了 116,000 个非冗余 TCF7L2 结合位点，其中只有 1,864 个位点是六种细胞系共有的。使用 ChIP-seq，我们发现许多由 H3K4me1 和 H3K27Ac 标记的基因组区域也与 TCF7L2 结合，表明 TCF7L2 在增强子活性中发挥着关键作用。对细胞类型特异性 TCF7L2 结合位点的生物信息分析揭示了多种转录因子的富集，包括 HepG2 细胞中的 HNF4α 和 FOXA2 基序以及 MCF7 细胞中的 GATA3 基序。 ChIP-seq 分析显示，TCF7L2 在 HepG2 细胞中与 HNF4α 和 FOXA2 共定位，在 MCF7 细胞中与 GATA3 共定位。有趣的是，在 MCF7 细胞中，TCF7L2 基序在大多数 TCF7L2 位点中富集，但在 GATA3 和 TCF7L2 结合的位点中不富集。该分析表明 GATA3 可能将 TCF7L2 与基因组的这些位点联系在一起。为了验证这一假设，我们耗尽了 MCF7 细胞中的 GATA3，并显示 TCF7L2 结合在一部分位点上丢失。 RNA-seq 分析表明，TCF7L2 通过 GATA3 连接到基因组时会抑制转录。我们的研究证明了 GATA3 和 TCF7L2 之间的新型关系，并揭示了对 TCF7L2 介导的基因调控的重要见解。
The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in six human cell lines. We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the six cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3. Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation.
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DOI：
10.1093/bioinformatics/btq669
发表时间：
2011-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Lan X;Bonneville R;Apostolos J;Wu W;Jin VX
通讯作者：
Jin VX
影响因子：
5.6
作者：
Chou, Jonathan;Provot, Sylvain;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
14.9
作者：
Blahnik KR;Dou L;O'Geen H;McPhillips T;Xu X;Cao AR;Iyengar S;Nicolet CM;Ludäscher B;Korf I;Farnham PJ
通讯作者：
Farnham PJ
影响因子：
3.5
作者：
Le Bacquer, Olivier;Shu, Luan;Maedler, Kathrin
通讯作者：
Maedler, Kathrin
影响因子：
50.3
作者：
Kouros-Mehr, Hosein;Bechis, Seth K.;Werb, Zena
通讯作者：
Werb, Zena