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Progress in Mechanism of REST/NRSF Regulation of Clustered Protocadherin Alpha Genes

April 23, 2021      Author:

On April 14th, the research team led by Professor Wu Qiang from Comparative Biomedical Center of SJTU Shanghai Center for Systems Biomedicine published a research article titled “Mechanism of REST/NRSF Regulation of Clustered Protocadherin Alpha Genes on the website of Nucleic Acid Research, an international academic journal issued by Oxford University Press. It reveals the regulation mechanism of transcription factor REST with DNA-binding pattern in the clustered protocadherin (PCDH) genes. 

REST is a zinc-finger (ZF) protein containing zinc finger domains arranged in series, which inhibits the expression of corresponding genes by combining thousands of sites in human genome. However, how REST recognizes the sites in human genome is a core problem that remains to be resolved.

The study found through a series of experiments that REST recognizes thousands of sites in human genome in a base-specific anti-parallel manner through its tandem arrangement of zinc finger domains. Further study found that REST recognizes different types of binding sites in the human genome through conformational changes, which are of great significance for elucidating the mechanism of zinc finger transcription factor recognition and construction of the human genome.

Through the self-developed DNA fragment editing technology, the team discovered for the first time that REST can inhibit the long-distance interaction between the super enhancer and the targeted promoter, and inhibit the expression of neural genes. This discovery is a brand-new mechanism, and laid the foundation for a comprehensive study of the inhibitory mechanism of neurogenes in the development of tissues and organs.

The research was completed by the cooperation of Wu Qiang’s research group and Da Lintai’s research group of SJTU Shanghai Center for Systems Biomedicine. Prof.

Wu Qiang is the corresponding author and SJTU doctoral student Tang Yuanxiao is the first author. The research was funded by the National Natural Science Foundation of China, the Ministry of Science and Technology and the Shanghai Municipal Science and Technology Commission.

 

Author: Tang Yuanxiao

SourceShanghai Center for Systems Biomedicine

Translated by Zhang Yue

Proofread by Xiao Yangning, Fu Yuhe

 

ABSTRACT:

Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5–1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDHα genes. Thus, REST/NRSF represses PCDHα gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.