Mechanism of REST/NRSF Regulation of Clustered Protocadherin α Genes

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 expr...

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Bibliographic Details
Published inbioRxiv
Main Authors Tang, Yuanxiao, Jia, Zhilian, Xu, Honglin, Lin-Tai, Da, Wu, Qiang
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.03.2021
Subjects
Gene expression
Gene silencing
Genomes
Protocadherin
Regulatory sequences
REST protein
Zinc finger proteins
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Summary: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. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2021.03.06.434230