Genome-wide maps of DNase I hypersensitive sites (DHSs) reveal that most human promoters contain perpetually active cis-regulatory elements between −150 bp and +50 bp (−150/+50 bp) relative to the transcription start site (TSS). Transcription factors (TFs) recruit cofactors (chromatin remodelers, histone/protein-modifying enzymes, and scaffold proteins) to these elements in order to organize the local chromatin structure and coordinate the balance of post-translational modifications nearby, contributing to the overall regulation of transcription. However, the rules of TF-mediated cofactor recruitment to the −150/+50 bp promoter regions remain poorly understood. Here, we provide evidence for a general model in which a series of cis-regulatory elements (here termed ‘cardinal’ motifs) prefer acting individually, rather than in fixed combinations, within the −150/+50 bp regions to recruit TFs that dictate cofactor signatures distinctive of specific promoter subsets. Subsequently, human promoters can be subclassified based on the presence of cardinal elements and their associated cofactor signatures. In this study, furthermore, we have focused on promoters containing the nuclear respiratory factor 1 (NRF1) motif as the cardinal cis-regulatory element and have identified the pervasive association of NRF1 with the cofactor lysine-specific demethylase 1 (LSD1/KDM1A). This signature might be distinctive of promoters regulating nuclear-encoded mitochondrial and other particular genes in at least some cells. Together, we propose that decoding a signature-based, expanded model of control at proximal promoter regions should lead to a better understanding of coordinated regulation of gene transcription.
Human cells exploit different mechanisms to coordinate the expression of both protein-coding and non-coding RNAs. Elucidating these mechanisms is essential to understanding normal physiology and disease. In our attempt to identify new regulatory layers acting particularly at proximal promoters, we have computationally analyzed the genomic sequences located from −150 bp to +50 bp relative to the transcriptional start site (TSS), which are often at the center of ‘open’ chromatin regions in human promoters. We have confirmed the presence of a series of cis-regulatory elements (here referred to as ‘cardinal’ motifs) that show a strong preference for these short regions. Interestingly, these elements tend to act independently rather than in fixed combinations. Therefore, we propose that they confer unique regulatory features to the human promoter subsets that contain each of these particular elements. In agreement with this model, we have identified a large repertoire of preferential partnerships between transcription factors recognizing cardinal motifs and their associated proteins (cofactors), thus decoding a signature-based model that distinguishes distinctive regulatory types of promoters based on cardinal motifs. These signatures may underlie a new layer of transcriptional regulation to orchestrate coordinated gene expression in human promoters.