Visel_2009: Genomic Views of Distant-Acting Enhancers
Genomic Views of Distant-Acting Enhancers
Preface
In contrast to changes in protein-coding sequences, the significance of noncoding DNA variation in human disease has been minimally explored.
Distant-acting transcriptional enhancers - a major category of functional noncoding DNA - are likely involved in many developmental and disease-relevant processes.
Introduction
genome-wide association studies (GWASs) have revealed a large number of disease susceptibility regions that do not overlap protein-coding genes, but rather map to noncoding intervals
a 58kb linkage disequilibrium block located at human chromosome 9p21 was shown to be reproducibly associated with an increased risk for coronary artery disease
But it lies 6kb away from the nearest known protein coding gne
To estimate the global contribution of variation in non-coding sequences to phenotypic and disease traits
Analysis of ~1200
40% of cases no known exons overlap the link SNP
One possibility that could explain these GWAS hits is that the non-coding intervals contain enhancers
Figure 1. Schematic overview of gene regulation by distant-acting enhancers
Shows that tissue specific enhancers can both regulate the same gene
Only when the required TFs are present the enhancer becomes activated
Binds to transcriptional co-activators, relocates to be in close proximity of the promoter
Which then activates transcription by RNA polymerase II
Insulator elements prevent enhancer-promoter interactions and can thus restrict the activity of enhancers to defined chromatin domains
Transcriptional enhancers represent regulatory sequences that can be located
Upstream
Downstream
Within their target genee
Can moduluate expression independ of their orientation
In vertebrates, enhancer sequences are thought to represent densely clustered aggregations of Transcription Factor binding sites
In-depth studies of individual genes such as APOE or NKX2-5
have shown that many genes are regulated by complex arrays of enhancers, each
driving distinct aspects of the mRNA expression pattern
In this review we will focus on the role of enhancers and on strategies to define their location and function genome-wide
Though they expect noncoding RNAs to play a role in human disease