Identifying regulatory elements in eukaryotic genomes

Abstract

Proper development and functioning of an organism depends on precise spatial and temporal expression of all its genes. These coordinated expression-patterns are maintained primarily through the process of transcriptional regulation. Transcriptional regulation is mediated by proteins binding to regulatory elements on the DNA in a combinatorial manner, where particular combinations of transcription factor binding sites establish specific regulatory codes. In this review, we survey experimental and computational approaches geared towards the identification of proximal and distal gene regulatory elements in the genomes of complex eukaryotes. Available approaches that decipher the genetic structure and function of regulatory elements by exploiting various sources of information like gene expression data, chromatin structure, DNA-binding specificities of transcription factors, cooperativity of transcription factors, etc. are highlighted. We also discuss the relevance of regulatory elements in the context of human health through examples of mutations in some of these regions having serious implications in misregulation of genes and being strongly associated with human disorders.

Connecting Transcriptional Control to Chromosome Structure and Human Disease

“…Most eukaryotic DNA-binding transcription factors appear to function as transcriptional activators but can be bound by other proteins that cause the multiprotein complex to act as a repressor. Transcription factors bind to both promoterproximal DNA elements and to distal regions 1-100 kb away from the promoter (D'Alessio et al 2009;Narlikar and Ovcharenko 2009;Pan et al 2010). The distal elements that are involved in positive gene regulation are generally called enhancers, and these elements are typically bound by multiple transcription factors.…”

Osmolality/salinity-responsive enhancers (OSREs) control induction of osmoprotective genes in euryhaline fish

“…(71). With the exception of TonE/ORE and osmotic-responsive element (OsmoE) (72) elements, no salinity-regulated CRE has been identified by experimental approaches in any animal, although computational algorithms (19) have been used to predict enhancers based on conserved sequence motifs. Using such algorithms, a TonE/ORE in the deiodinase 2 gene of Fundulus heteroclitus, which is induced by hypo-(rather than hyper-) osmotic stress but matches the mammalian TonE/ORE consensus, has been predicted (73).…”

“…Changed gene-expression patterns, in turn, lead to altered phenotypes to achieve biochemical adaptation and the evolution of populations and species (15)(16)(17)(18). Such variation modifies the highly dynamic nature of gene-regulatory networks, which embody the interaction of a large number of CREs and trans factors (19)(20)(21)(22). Therefore, the identification and experimental validation of environmentally regulated CREs in organisms that are uniquely adapted to particular habitats is a critical prerequisite for understanding biochemical evolution (23).…”

Proximal Regulatory Elements with Emphasis on CpG Rich Regions

“…Identifying a promoter of a specifi c gene can be diffi cult as core promoters are found far from the fi rst exon because of the existence of the 5′ untranslated region (UTR) and/or introns. Furthermore, not all the promoters contain the core promoter elements thus the identifi cation can be a challenge [ 57 ]. For prediction and identifi cation of such regulatory regions, computational approaches are very helpful.…”