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Related Concept Videos

Cis-regulatory Sequences02:02

Cis-regulatory Sequences

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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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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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Cooperative Binding of Transcription Regulators02:13

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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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Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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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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Non-coding variants impact cis-regulatory coordination in a cell type-specific manner.

Olga Pushkarev1,2, Guido van Mierlo3,4, Judith Franziska Kribelbauer1,2

  • 1Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Genome Biology
|July 18, 2024
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Summary

This study optimizes methods for mapping chromatin modules (CMs), which are groups of interacting cis-regulatory elements (CREs). These CMs reveal how genetic variations influence gene expression and disease risk in a cell-type-specific manner.

Keywords:
Cis-regulatory interactionsEpigenomicsGene regulationGenome-wide association studiesQuantitative trait loci

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Area of Science:

  • Genomics
  • Epigenetics
  • Gene Regulation

Background:

  • Cis-regulatory element (CRE) interactions are vital for gene regulation.
  • Chromatin modules (CMs) map these interactions using epigenomic variation.
  • Existing CM mapping computational methods have varied outcomes.

Purpose of the Study:

  • To evaluate and refine CM mapping tools for optimal epigenome data utilization.
  • To assess regulatory coordination across the human genome.
  • To understand the impact of CMs on gene expression and disease predisposition.

Main Methods:

  • Comprehensive evaluation and streamlining of existing CM mapping tools.
  • Analysis of epigenome data from diverse populations and distinct cell types.
  • Integration of genotype information to identify effects of non-coding variants.

Main Results:

  • Developed guidelines for optimal CM mapping using diverse epigenome data.
  • Demonstrated cell type-specific CRE interactions within CMs and their link to gene expression.
  • Showcased how non-coding variants impact CM activity and transcription factor binding in a cell type-specific manner.
  • Illustrated CM application in deconstructing GWAS loci, analyzing immune cell receptors, and understanding leukemia prognostic markers.

Conclusions:

  • An optimal strategy for CM mapping was established, capturing CRE coordination and its effect on gene expression.
  • Non-coding genetic variants can disrupt CRE coordination, potentially leading to cell type-specific disease predisposition.