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Cis-regulatory Sequences02:02

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Cis-regulatory sequences are short fragments of non-coding DNA that are present on the same chromosomes as the genes that they regulate. These fragments serve as binding sites for transcriptional regulators, proteins that are responsible for controlling gene transcription and differential gene expression across cell types in eukaryotes. Cis-regulatory sequences can be close to the gene of interest or thousands of bases away in the DNA sequence; however, those sequences that are further away are...
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Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
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Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
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Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
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Uncovering drug-responsive regulatory elements.

Marcelo R Luizon1,2, Nadav Ahituv1,2

  • 1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.

Pharmacogenomics
|November 12, 2015
PubMed
Summary
This summary is machine-generated.

Genetic variations in gene regulatory elements significantly impact how individuals respond to drugs. Most drug-associated genetic markers are found in noncoding DNA, highlighting the importance of studying these regions for personalized medicine.

Keywords:
ChIP-seqRNA-seqenhancersgene regulatory elementspharmacogenomicspromoterstranscriptional regulation

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Area of Science:

  • Pharmacogenomics
  • Genetics
  • Molecular Biology

Background:

  • Interindividual differences in drug response are common.
  • Nucleotide changes in gene regulatory elements are implicated in these differences.
  • A significant portion of pharmacogenomic associations are in noncoding regions.

Purpose of the Study:

  • To review the role of nucleotide changes in gene regulatory elements on drug response.
  • To highlight advancements in identifying and annotating variants in these elements.
  • To discuss challenges in translating these findings into clinical practice.

Main Methods:

  • Review of published pharmacogenomic genome-wide association studies.
  • Analysis of single nucleotide polymorphism (SNP) locations.
  • Discussion of sequencing technologies and functional characterization techniques.

Main Results:

  • 96.4% of associated SNPs in pharmacogenomic studies are located in noncoding regions.
  • Sequencing technologies enhance the identification of drug response-associated regulatory elements.
  • Specific examples demonstrate the functional impact of variants in regulatory elements.

Conclusions:

  • Nucleotide changes in gene regulatory elements are critical determinants of drug response.
  • Advanced genomic and sequencing technologies are crucial for discovery.
  • Overcoming clinical translation challenges is necessary for personalized medicine.