For example, in mouse mature white adipose tissue, PPARγ bindings that vary between close strains do not harbor an altered motif but exhibit linkage to extensive co-localization with motifs corresponded to CEBPα and glucocorticoid receptor. However, recent genome-wide studies reveal that variable TF-DNA binding is not only driven by sequence alterations in the motif of the cognate TF, but additional features such as the nucleotide composition of motif-neighboring sequences, the chromatin context of a genuine binding site, and the three dimensional (3D) structural confirmation of DNA, which are also important to model TF-DNA binding. Accumulating evidence suggests that genetic variants within regulatory sequences may alter the binding of TFs to induce gene expression variation and ultimately result in complex phenotypic changes.
The vast majority of complex trait-associated variants from the Genome-Wide Association Studies (GWAS) are located in non-coding regulatory regions-only approximately 5% of GWAS SNPs are located in the protein-coding regions. Specifically encoded stable enhancers are evolutionarily conserved and associated with development, while differently encoded fragile enhancers are associated with the adaptation of species.Īnalysis of genomic variants in humans and model species such as mouse and fruit fly is providing opportunities for understanding the genetic basis of complex traits and disease predisposition. This dichotomy of enhancer activity is conserved across different tissues, has a specific footprint in epigenetic profiles, and argues for a bimodal evolution of gene regulatory programs in vertebrates. Notably, the sequence environment and chromatin context of the cognate motif, other than the motif itself, contribute more to the susceptibility to deMs of TF binding. Moreover, stable enhancers are more tolerant of deMs due to their dominant employment of homotypic TF binding site (TFBS) clusters, as opposed to the larger-extent usage of heterotypic TFBS clusters in fragile enhancers. These two classes of enhancers feature different regulatory programs: the binding sites of pioneer TFs of FOX family are specifically enriched in stable enhancers, while tissue-specific TFs are enriched in fragile enhancers. Secondly, stable enhancers with only a few deM nucleotides are associated with the development and regulation of TFs and are evolutionarily conserved. Firstly, fragile enhancers with abundant deM nucleotides are associated with the immune system and regular cellular maintenance. We identify two classes of enhancers based on the density of nucleotides prone to deMs. Here, we focus on elucidating the mechanism underlying the different densities of deMs in human enhancers. Despite continual progress in the identification and characterization of trait- and disease-associated variants that disrupt transcription factor (TF)-DNA binding, little is known about the distribution of TF binding deactivating mutations (deMs) in enhancer sequences.
0 kommentar(er)
