Abstract
BackgroundDespite 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. Here, we focus on elucidating the mechanism underlying the different densities of deMs in human enhancers.ResultsWe identify two classes of enhancers based on the density of nucleotides prone to deMs. Firstly, fragile enhancers with abundant deM nucleotides are associated with the immune system and regular cellular maintenance. Secondly, stable enhancers with only a few deM nucleotides are associated with the development and regulation of TFs and are evolutionarily conserved. 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. 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. 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.ConclusionsThis 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. Specifically encoded stable enhancers are evolutionarily conserved and associated with development, while differently encoded fragile enhancers are associated with the adaptation of species.
Highlights
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 Transcription factors (TFs) binding deactivating mutations in enhancer sequences
The mutations identified by CellulAr-dePendent dEactivating mutations (CAPE) (FPR ≤ 0.01) were dubbed deactivating mutations, as they are likely to disrupt the binding of an essential TF and lead to a deleterious
TF interaction modes and chromatin contexts contribute more to the fragility of TF binding than the cognate motif Since the Transcription factor binding sites (TFBSs) enriched in fragile enhancers are prone to deactivating mutation positions (deMPs), whereas the TFBSs in stable enhancers are impervious to deMPs (Fig. 4b), we studied what contributed more to the different extents of the fragility of TF binding in the two sets of enhancers, namely, the cognate motif or interactions among TFs?
Summary
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. To accurately identify the causal regulatory variation, advanced and flexible machine learning models, such as support vector machine (SVM) [5, 15] and deep learning neural network [13, 20], have been constructed by integrating versatile features associated with enhancer activity. These models are commonly trained on multiple layers of genomic, epigenomic, and transcriptomic information. The causal regulatory variants predicted by CAPE are termed deactivating mutations (deMs)
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