In:
eLife, eLife Sciences Publications, Ltd, Vol. 3 ( 2014-10-03)
Abstract:
Stretches of DNA called cis-regulatory modules (or CRMs for short) could help researchers to identify the regions of DNA that are most important for controlling genes. CRMs are regions where multiple transcription factors—proteins that control when and how genes are expressed—bind to DNA. As important biological pathways are often regulated by more than one transcription factor, CRMs are therefore a good target when looking for DNA regions that, if mutated, are likely to cause disease. If a stretch of DNA performs an important role, it is often conserved throughout evolution. This is often observed for genes that make proteins. Indeed, DNA regions that specify critical amino acids that make up proteins are often conserved across distantly related species. However, unlike the changes made to the amino acid encoding parts of genes, it is currently a challenge to predict which changes in the rest of the genome will affect gene expression. One reason for this challenge is that transcription factor binding sites are rapidly evolving. This rapid evolution means that strictly comparing DNA sequences between species may fail to identify where transcription factors like to bind in the genome. Numerous experimental efforts have therefore been made to map these sites. These have revealed that there are a huge number of regions in the human genome that can bind transcription factors: hundreds of thousands of sites, far more than there are genes. For this reason, there is a great interest in revealing which of these regulatory regions are critical for maintaining normal levels and timings of gene expression. Ballester et al. compared the binding sites of four transcription factors responsible for regulating liver function in humans, macaques, mice, rats, and dogs. About two-thirds of these binding sites were found in CRMs. Less than half of the CRMs in humans were also CRMs in another species—but Ballester et al. found that these shared CRMs are predominantly in charge of regulating the essential biological pathways that allow the liver to function correctly. In addition, Ballester et al. identified several examples of disease-causing DNA mutations in shared CRMs that affected the expression of genes that make up pathways such as the blood clotting cascade. Genome-wide association studies also uncovered common variants for liver-related traits that were enriched for the CRMs found in more than one species, further supporting their importance. As transcription factors work in different ways in different tissues, further studies are now required to expand these observations to organs other than the liver. Future work is also needed to investigate the function of thousands of conserved CRMs whose role in liver gene regulation remains unknown.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.02626.001
DOI:
10.7554/eLife.02626.002
DOI:
10.7554/eLife.02626.003
DOI:
10.7554/eLife.02626.004
DOI:
10.7554/eLife.02626.005
DOI:
10.7554/eLife.02626.006
DOI:
10.7554/eLife.02626.007
DOI:
10.7554/eLife.02626.008
DOI:
10.7554/eLife.02626.009
DOI:
10.7554/eLife.02626.010
DOI:
10.7554/eLife.02626.011
DOI:
10.7554/eLife.02626.012
DOI:
10.7554/eLife.02626.013
DOI:
10.7554/eLife.02626.014
DOI:
10.7554/eLife.02626.015
DOI:
10.7554/eLife.02626.016
DOI:
10.7554/eLife.02626.017
DOI:
10.7554/eLife.02626.018
DOI:
10.7554/eLife.02626.019
DOI:
10.7554/eLife.02626.020
DOI:
10.7554/eLife.02626.021
DOI:
10.7554/eLife.02626.022
DOI:
10.7554/eLife.02626.023
DOI:
10.7554/eLife.02626.024
DOI:
10.7554/eLife.02626.025
DOI:
10.7554/eLife.02626.026
DOI:
10.7554/eLife.02626.027
DOI:
10.7554/eLife.02626.028
DOI:
10.7554/eLife.02626.029
DOI:
10.7554/eLife.02626.030
DOI:
10.7554/eLife.02626.031
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2014
detail.hit.zdb_id:
2687154-3