Study unearths previously unknown role of CTCF, the transcription regulator

CCCTC-binding factor (CTCF) is a transcription factor and its role in regulating the critical oncogene, MYC, makes it a vital research target. Researchers from St. Jude Children’s Research Hospital discovered direct evidence that CTCF governs chromatin accessibility, the mechanism of opening tightly spooled DNA facilitating gene expression.

Study unearths previously unknown role of CTCF, the transcription regulator
Chunliang Li, PhD, St. Jude Department of Tumor Cell Biology. Image Credit: St. Jude Children’s Research Hospital.

The results were published in Genome Biology.

CTCF is widely known by biologists as a master regulator of the genome and for greatly influencing the genome’s 3D architecture. Mutations of CTCF that result in its absence are unusual, but mutations that affect the way it binds to proteins and genes are common in cells with diseases like cancer. The downstream repercussions of CTCF on genes are greatly studied, while little is known about the more immediate impacts.

There has been a gap in our knowledge of the direct effect of CTCF, which is important for understanding the process of transcription. If you alter gene expression at the right time and place, then even a moderate change in transcription can cause a substantial change in disease development.”

Chunliang Li, PhD, Study Senior and Co-Corresponding Author, Department of Tumor Cell Biology, St. Jude Children’s Research Hospital

Novel techniques lead the way

The scientists employed state-of-the-art technologies and a multifaceted approach that utilizes an auxin-induced degron system. The auxin-induced degron system is a method that degrades a protein in a targeted way in less time, enabling scientists to get a greater understanding of its primary function. These tools were significant to analyze how acute depletion of the CTCF protein will impact the cell.

It is challenging to distinguish the true biology of CTCF, but we’ve used these tools to provide direct evidence that CTCF regulates chromatin accessibility and to provide clarity for the field.”

Beisi Xu, PhD, Study Co-First and Co-Corresponding Author, Center for Applied Bioinformatics, St. Jude Children’s Research Hospital

The researchers also observed the multi-omics data, including techniques named RNA-seq, ATAC-seq, whole-genome bisulfite sequencing, Cut&Run, Hi-C, and CRISPR-Cas9 screens, and time-solved deep proteomic and phosphoproteomic examinations in cells transporting the auxin-induced degron.

Junmin Peng, Ph.D., the study author and the director of Center for Proteomics and Metabolomics at St. Jude, states, “The multidisciplinary collaboration between our teams helped make these findings possible. A better understanding of the direct effect of CTCF will help propel the field of transcription biology toward a more complete picture of how the processes are involved in diseases such as cancer.”

Understanding a direct effect for CTCF

This research emphasizes that CTCF loss rewires genome-wide chromatin accessibility, which performs a vital role in transcriptional regulation. As pediatric cancers possess a relatively quiet genome, identifying novel treatments needs a greater understanding of cancer biology on a base level. This involves going deep down to how the mechanism of CTCF and transcription go wrong.

CTCF is a fundamental part of the machinery that drives activity in the cell, but without the right tools to study it, its direct role has been debatable. By integrating the latest techniques, we’ve shown a direct function for CTCF that couldn’t have been revealed by older technology.”

Hong Wang, PhD, Study Co-First Author, Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital

Source:
Journal reference:

Xu, B., et al. (2021) Acute depletion of CTCF rewires genome-wide chromatin accessibility. Genome Biology. doi.org/10.1186/s13059-021-02466-0.

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