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Title: A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes
Authors: Johnson R.
Richter N.
Bogu G.K.
Bhinge A.
Teng S.W.
Choo S.H.
Andrieux L.O.
de Benedictis C.
Jauch R.
Stanton L.W. 
Keywords: repressor element 1 silencing transcription factor
repressor protein
unclassified drug
DNA binding protein
RE1 silencing transcription factor
RE1-silencing transcription factor
repressor protein
transcription factor
binding affinity
binding site
CDH4 gene
chromatin immunoprecipitation
controlled study
disease predisposition
DNA recognition element
DNA structure
gene identification
gene regulatory network
gene targeting
genetic analysis
genetic association
genetic parameters
genetic polymorphism
genetic variability
human cell
in vitro study
in vivo study
NPPA gene
protein DNA binding
PTPRT gene
reporter gene
repressor element 1
single nucleotide polymorphism
binding site
cell line
DNA microarray
human genome
nucleotide motif
regulatory sequence
Binding Sites
Cell Line
DNA-Binding Proteins
Gene Regulatory Networks
Genome, Human
Nucleotide Motifs
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Regulatory Sequences, Nucleic Acid
Repressor Proteins
Transcription Factors
Issue Date: 2012
Citation: Johnson R., Richter N., Bogu G.K., Bhinge A., Teng S.W., Choo S.H., Andrieux L.O., de Benedictis C., Jauch R., Stanton L.W. (2012). A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. PLoS Genetics 8 (4) : e1002624. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Increasing numbers of human diseases are being linked to genetic variants, but our understanding of the mechanistic links leading from DNA sequence to disease phenotype is limited. The majority of disease-causing nucleotide variants fall within the non-protein-coding portion of the genome, making it likely that they act by altering gene regulatory sequences. We hypothesised that SNPs within the binding sites of the transcriptional repressor REST alter the degree of repression of target genes. Given that changes in the effective concentration of REST contribute to several pathologies-various cancers, Huntington's disease, cardiac hypertrophy, vascular smooth muscle proliferation-these SNPs should alter disease-susceptibility in carriers. We devised a strategy to identify SNPs that affect the recruitment of REST to target genes through the alteration of its DNA recognition element, the RE1. A multi-step screen combining genetic, genomic, and experimental filters yielded 56 polymorphic RE1 sequences with robust and statistically significant differences of affinity between alleles. These SNPs have a considerable effect on the the functional recruitment of REST to DNA in a range of in vitro, reporter gene, and in vivo analyses. Furthermore, we observe allele-specific biases in deeply sequenced chromatin immunoprecipitation data, consistent with predicted differenes in RE1 affinity. Amongst the targets of polymorphic RE1 elements are important disease genes including NPPA, PTPRT, and CDH4. Thus, considerable genetic variation exists in the DNA motifs that connect gene regulatory networks. Recently available ChIP-seq data allow the annotation of human genetic polymorphisms with regulatory information to generate prior hypotheses about their disease-causing mechanism. © 2012 Johnson et al.
Source Title: PLoS Genetics
ISSN: 15537390
DOI: 10.1371/journal.pgen.1002624
Rights: Attribution 4.0 International
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