A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes.
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3320604?pdf=render |
| _version_ | 1818507614979358720 |
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| author | Rory Johnson Nadine Richter Gireesh K Bogu Akshay Bhinge Siaw Wei Teng Siew Hua Choo Lise O Andrieux Cinzia de Benedictis Ralf Jauch Lawrence W Stanton |
| author_facet | Rory Johnson Nadine Richter Gireesh K Bogu Akshay Bhinge Siaw Wei Teng Siew Hua Choo Lise O Andrieux Cinzia de Benedictis Ralf Jauch Lawrence W Stanton |
| author_sort | Rory Johnson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T22:20:40Z |
| format | Article |
| id | doaj.art-e16b75ef144e4b24a1906c72ac44cdcb |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-10T22:20:40Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-e16b75ef144e4b24a1906c72ac44cdcb2022-12-22T01:31:19ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-0184e100262410.1371/journal.pgen.1002624A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes.Rory JohnsonNadine RichterGireesh K BoguAkshay BhingeSiaw Wei TengSiew Hua ChooLise O AndrieuxCinzia de BenedictisRalf JauchLawrence W StantonIncreasing 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.http://europepmc.org/articles/PMC3320604?pdf=render |
| spellingShingle | Rory Johnson Nadine Richter Gireesh K Bogu Akshay Bhinge Siaw Wei Teng Siew Hua Choo Lise O Andrieux Cinzia de Benedictis Ralf Jauch Lawrence W Stanton A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. PLoS Genetics |
| title | A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. |
| title_full | A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. |
| title_fullStr | A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. |
| title_full_unstemmed | A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. |
| title_short | A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. |
| title_sort | genome wide screen for genetic variants that modify the recruitment of rest to its target genes |
| url | http://europepmc.org/articles/PMC3320604?pdf=render |
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