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Exploring the effects of polymorphisms on cis-regulatory signal transduction response.

MacKenzie A, Hing B, Davidson S - Trends Mol Med (2012)

Bottom Line: cis-Regulatory sequences (CRSs) direct cell-specific and inducible gene expression in response to signal transduction networks, and it is becoming apparent that many cases of disease susceptibility and drug response stratification are due to polymorphisms that alter CRS responses in a context-dependent manner.The technologies described build on the successes of ENCODE (ENCyclopedia Of DNA Elements) by exploring the effects of polymorphisms on CRS context dependency.This understanding is essential to uncover the genomic basis of disease susceptibility and will play a major role in delivering on the promise of personalized medicine.

View Article: PubMed Central - PubMed

Affiliation: Gene Regulatory Systems Laboratory, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland AB25 2ZD, UK. alasdair.mackenzie@abdn.ac.uk

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A flow diagram describing the relationships between different technologies that can be used to identify and characterize cis-regulatory sequences (CRSs) and to determine the effects of polymorphisms on their qualitative and quantitative activities using a series of different in vivo, in vitro, and high-throughput technologies. The first row describes the technologies that can be used to identify CRSs (GWAS, genome-wide association analysis; ChIP-seq, chromatin immunoprecipitation sequencing; FAIRE-seq, formaldehyde-assisted identification of regulatory element sequencing; 5C, carbon copy chromatin conformation capture). The second row describes the genome and DNA manipulations required to test hypotheses relating to CRS activity and the effects of polymorphisms (SDM, site-directed mutation; Luc, luciferase; Lac, LacZ gene encoding β-galactosidase; GFP, green fluorescent protein). The third row summarizes many of the different questions relevant to the understanding of the function of CRSs and the effects of SNPs on their activity. The last row summarizes several different paradigms that can be used to address the questions posed in the third row (ES, embryonic stem cell; QrtPCR, quantitative reverse transcriptase polymerase chain reaction; 3C, chromatin conformation capture; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation). This flow diagram is not exhaustive and does not include technologies that allow analysis of epigenetic modification.
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fig0010: A flow diagram describing the relationships between different technologies that can be used to identify and characterize cis-regulatory sequences (CRSs) and to determine the effects of polymorphisms on their qualitative and quantitative activities using a series of different in vivo, in vitro, and high-throughput technologies. The first row describes the technologies that can be used to identify CRSs (GWAS, genome-wide association analysis; ChIP-seq, chromatin immunoprecipitation sequencing; FAIRE-seq, formaldehyde-assisted identification of regulatory element sequencing; 5C, carbon copy chromatin conformation capture). The second row describes the genome and DNA manipulations required to test hypotheses relating to CRS activity and the effects of polymorphisms (SDM, site-directed mutation; Luc, luciferase; Lac, LacZ gene encoding β-galactosidase; GFP, green fluorescent protein). The third row summarizes many of the different questions relevant to the understanding of the function of CRSs and the effects of SNPs on their activity. The last row summarizes several different paradigms that can be used to address the questions posed in the third row (ES, embryonic stem cell; QrtPCR, quantitative reverse transcriptase polymerase chain reaction; 3C, chromatin conformation capture; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation). This flow diagram is not exhaustive and does not include technologies that allow analysis of epigenetic modification.

Mentions: The main obstacle to understanding the mechanisms that affect CRS activity has been our inability to identify them. In the past, identifying CRSs has relied on the painstaking deletion analysis of gene flanking regions. However, thanks to the sequencing of the human genome and the availability of ever more rapid advances in high-throughput sequencing technologies, several more rapid and effective high-throughput solutions have been devised to find and characterize CRSs (summarized in Box 1 and Figure 2).


Exploring the effects of polymorphisms on cis-regulatory signal transduction response.

MacKenzie A, Hing B, Davidson S - Trends Mol Med (2012)

A flow diagram describing the relationships between different technologies that can be used to identify and characterize cis-regulatory sequences (CRSs) and to determine the effects of polymorphisms on their qualitative and quantitative activities using a series of different in vivo, in vitro, and high-throughput technologies. The first row describes the technologies that can be used to identify CRSs (GWAS, genome-wide association analysis; ChIP-seq, chromatin immunoprecipitation sequencing; FAIRE-seq, formaldehyde-assisted identification of regulatory element sequencing; 5C, carbon copy chromatin conformation capture). The second row describes the genome and DNA manipulations required to test hypotheses relating to CRS activity and the effects of polymorphisms (SDM, site-directed mutation; Luc, luciferase; Lac, LacZ gene encoding β-galactosidase; GFP, green fluorescent protein). The third row summarizes many of the different questions relevant to the understanding of the function of CRSs and the effects of SNPs on their activity. The last row summarizes several different paradigms that can be used to address the questions posed in the third row (ES, embryonic stem cell; QrtPCR, quantitative reverse transcriptase polymerase chain reaction; 3C, chromatin conformation capture; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation). This flow diagram is not exhaustive and does not include technologies that allow analysis of epigenetic modification.
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fig0010: A flow diagram describing the relationships between different technologies that can be used to identify and characterize cis-regulatory sequences (CRSs) and to determine the effects of polymorphisms on their qualitative and quantitative activities using a series of different in vivo, in vitro, and high-throughput technologies. The first row describes the technologies that can be used to identify CRSs (GWAS, genome-wide association analysis; ChIP-seq, chromatin immunoprecipitation sequencing; FAIRE-seq, formaldehyde-assisted identification of regulatory element sequencing; 5C, carbon copy chromatin conformation capture). The second row describes the genome and DNA manipulations required to test hypotheses relating to CRS activity and the effects of polymorphisms (SDM, site-directed mutation; Luc, luciferase; Lac, LacZ gene encoding β-galactosidase; GFP, green fluorescent protein). The third row summarizes many of the different questions relevant to the understanding of the function of CRSs and the effects of SNPs on their activity. The last row summarizes several different paradigms that can be used to address the questions posed in the third row (ES, embryonic stem cell; QrtPCR, quantitative reverse transcriptase polymerase chain reaction; 3C, chromatin conformation capture; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation). This flow diagram is not exhaustive and does not include technologies that allow analysis of epigenetic modification.
Mentions: The main obstacle to understanding the mechanisms that affect CRS activity has been our inability to identify them. In the past, identifying CRSs has relied on the painstaking deletion analysis of gene flanking regions. However, thanks to the sequencing of the human genome and the availability of ever more rapid advances in high-throughput sequencing technologies, several more rapid and effective high-throughput solutions have been devised to find and characterize CRSs (summarized in Box 1 and Figure 2).

Bottom Line: cis-Regulatory sequences (CRSs) direct cell-specific and inducible gene expression in response to signal transduction networks, and it is becoming apparent that many cases of disease susceptibility and drug response stratification are due to polymorphisms that alter CRS responses in a context-dependent manner.The technologies described build on the successes of ENCODE (ENCyclopedia Of DNA Elements) by exploring the effects of polymorphisms on CRS context dependency.This understanding is essential to uncover the genomic basis of disease susceptibility and will play a major role in delivering on the promise of personalized medicine.

View Article: PubMed Central - PubMed

Affiliation: Gene Regulatory Systems Laboratory, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland AB25 2ZD, UK. alasdair.mackenzie@abdn.ac.uk

Show MeSH