Biology subjects

Chen, W.-D.

Publications and source records attributed to Chen, W.-D..

3 recordsLinked to original sources

bioRxiv2026

TCF4 and CtBP1 Repress LEF1 to Maintain a TCF4-centric Transcriptional Program in Colon Cancer.

Abstract The canonical WNT signaling pathway guides cell growth throughout the human lifespan. In adults, WNT plays an essential role in tissue homeostasis by maintaining tissue stem cells. In the intestine, the WNT transcription factor, TCF4, is necessary for stem cell maintenance. Aberrant activation of WNT signaling is generally accepted as an initiating event in colon cancer, leading to constitutive TCF4 activity. To investigate the role of this key transcription factor in global gene regulation, we abrogated TCF4 expression in colon cancer cells. Loss of TCF4 function resulted in the over-expression of the WNT transcription factor, LEF1. LEF1 was transcriptionally competent and over-compensated for TCF4 (TCF7L2) silencing in a WNT reporter assay. TCF4 enlisted the transcriptional repressor CtBP1, and bound the LEF1 promoter, indicative of direct repression. TCF4 and LEF1 drove different transcriptional programs, with TCF4 favoring MYC and cell cycle progression, while LEF1 favored immune-related gene signatures. TCF4 was the primary regulator of MYC expression, yet also the mediator of LEF1 repression, suggestive of competition centered on TCF4 transcriptional output despite the {beta}-catenin saturated colon cancer nucleus. We conclude that TCF4 has dual activator-repressor activity in colon cancer.

cell biology↗

bioRxiv2022

Optical control of CRISPR-Cas editing with cyclically caged guide RNAs

The CRISPR/Cas system has been proved as one of the most powerful tools for precise gene editing. However, the approaches for precise control over the genome editing and regulatory events are still desirable. Here, we reported a spatiotemporal and efficient CRISPR/Cas9 and Cpf1-mediated editing with photo-sensitive circular gRNAs. This approach relies on only two or three pre-installed photolabile substituents followed by a simple covalent cyclization, which provides a robust synthesize approach in comparison to heavily modified gRNAs. In established cells stably expressing Cas9, the circular gRNA in coordination with light irradiation could direct a precise cleavage of GFP and VEGFA within a pre-defined cutting region. We have also achieved light-mediated MSTN gene editing in embryos, whereas a new bow-knot-type gRNA showed no background editing in the absence of light irradiation. Together, our work provides a significantly improved method to precisely manipulate where and when genes are edited.

biochemistry↗

bioRxiv2019

Cancer-type specific aneuploidies hard-wire chromosome-wide gene expression patterns of their tissue of origin

Most carcinomas have characteristic chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is unknown. As aneuploidies directly affect gene expression, we hypothesized that cancer-type specific aneuploidies, which emerge at early stages of tumor evolution, confer adaptive advantages to the physiological requirements of the tissue of origin. To test this hypothesis, we compared chromosomal aneuploidies reported in the TCGA database to chromosome arm-wide gene expression levels of normal tissues from the GTEx database. We find that cancer-type specific chromosomal aneuploidies mirror differential gene expression levels specific to the respective normal tissues which cannot be explained by copy number alterations of resident cancer driver genes. We propose that cancer-type specific aneuploidies "hard-wire" chromosome arm-wide gene expression levels present in normal tissues, favoring clonal expansion and tumorigenesis. One sentence summaryThe clonal evolution of cancer is initiated by tissue-specific transcriptional requirements

cancer biology↗