Mechanism of REST/NRSF regulation of clustered protocadherin α genes

Nucleic Acids Res. 2021 May 7;49(8):4506-4521. doi: 10.1093/nar/gkab248.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / chemistry
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation Sequencing
  • DNA Methylation
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation / genetics*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Molecular Dynamics Simulation
  • Multigene Family
  • Promoter Regions, Genetic*
  • Protein Binding
  • Protein Domains
  • RNA-Seq
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Zinc Fingers*

Substances

  • Cadherins
  • RE1-silencing transcription factor
  • Repressor Proteins