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TCF7L1 调控结直肠癌细胞中的表达。

TCF7L1 Regulates Expression in Colorectal Cancer Cells.

机构信息

Department of Biochemistry & Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17036, USA.

Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17036, USA.

出版信息

Genes (Basel). 2023 Feb 14;14(2):481. doi: 10.3390/genes14020481.

DOI:10.3390/genes14020481
PMID:36833408
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9956233/
Abstract

Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC), in part, by deregulating expression of genes controlled by the T-cell factor (TCF) family of transcription factors. TCFs contain a conserved DNA binding domain that mediates association with TCF binding elements (TBEs) within Wnt-responsive DNA elements (WREs). Intestinal stem cell marker, leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5), is a Wnt target gene that has been implicated in CRC stem cell plasticity. However, the WREs at the gene locus and how TCF factors directly regulate gene expression in CRC have not been fully defined. Here, we report that TCF family member, TCF7L1, plays a significant role in regulating expression in CRC cells. We demonstrate that TCF7L1 binds to a novel promoter-proximal WRE through association with a consensus TBE at the locus to repress expression. Using CRISPR activation and interference (CRISPRa/i) technologies to direct epigenetic modulation, we demonstrate that this WRE is a critical regulator of expression and spheroid formation capacity of CRC cells. Furthermore, we found that restoring expression rescues the TCF7L1-mediated reduction in spheroid formation efficiency. These results demonstrate a role for TCF7L1 in repressing gene expression to govern the spheroid formation potential of CRC cells.

摘要

Wnt/β-catenin 信号通路组件的突变部分通过调控 T 细胞因子（TCF）家族转录因子控制的基因表达来驱动结直肠癌（CRC）。TCF 包含一个保守的 DNA 结合域，介导与 Wnt 反应性 DNA 元件（WRE）内 TCF 结合元件（TBE）的结合。肠干细胞标志物富含亮氨酸重复的 G 蛋白偶联受体 5（LGR5）是 Wnt 的靶基因，它与 CRC 干细胞可塑性有关。然而， 基因座上的 WRE 以及 TCF 因子如何直接调节 CRC 中 的基因表达尚未完全定义。在这里，我们报告 TCF 家族成员 TCF7L1 在调节 CRC 细胞中的 表达中起重要作用。我们证明 TCF7L1 通过与 基因座上的共识 TBE 结合，在一个新的启动子近端 WRE 上结合，从而抑制 表达。使用 CRISPR 激活和干扰（CRISPRa/i）技术来指导表观遗传调节，我们证明这个 WRE 是调节 CRC 细胞 表达和球体形成能力的关键调控因子。此外，我们发现恢复 表达可以挽救 TCF7L1 介导的球体形成效率降低。这些结果表明 TCF7L1 在抑制 基因表达以控制 CRC 细胞球体形成潜力方面的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/49c2f7499897/genes-14-00481-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/ac67df69406b/genes-14-00481-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/a677592705e5/genes-14-00481-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/4a7ad7c85bbb/genes-14-00481-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/2b75cd9098f8/genes-14-00481-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/598123ca5082/genes-14-00481-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/49c2f7499897/genes-14-00481-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/ac67df69406b/genes-14-00481-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/a677592705e5/genes-14-00481-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/4a7ad7c85bbb/genes-14-00481-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/2b75cd9098f8/genes-14-00481-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/598123ca5082/genes-14-00481-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/629d/9956233/49c2f7499897/genes-14-00481-g006.jpg

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