Decoding a Signature-Based Model of Transcription Cofactor Recruitment Dictated by Cardinal Cis-Regulatory Elements in Proximal Promoter Regions

Abstract

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.

Deep neural networks identify context-specific determinants of transcription factor binding affinity

“…Overall, NFY and NFY-like motifs, which are known cardinal elements of promoter regions 48 , have a much stronger influence on proximal binding sites, but very little influence on distal sites.…”

Enhancer and promoter usage in the normal and failed human heart

“…The 70.1% of clusters mapping within 100bp of transcriptional start sites were highly enriched for GFY-Staf, Sp1, and Elk/ETS binding motifs, which are known promoter binding transcription factors. 27 Clusters mapping into other gene regions showed minimal enrichment of these motifs ( Figure 1B). To provide additional support for the promoter-enriched sequence clusters, ATAC sequencing and H3K4me3 ChIP-seq datasets were compared; Supplemental Table 2 Only 44.5% of bidirectional clusters mapped ±100bp within transcriptional start sites.…”

Coordinated Transcriptional Regulation of Cytochrome P450 3As by Nuclear Transcription Factor Y and Specificity Protein 1

“…NF-Y is a trimeric protein formed by NF-Y subunit alpha (NF-YA), NF-Y subunit beta, and NF-Y subunit gamma, and exhibits sequence-specific binding to CCAAT boxes (Maity and de Crombrugghe, 1998). A genome-wide study indicated that CCAAT boxes are mainly located within a conserved distance of 2150 to 150 base pairs (bp) from the transcription start sites in 18% of the 21,000 human promoters (Benner et al, 2013). Structural analysis revealed that NF-Y bound DNA in a histone-like mode (Ceribelli et al, 2008).…”

“…Coimmunoprecipitation suggested the direct interaction between Sp1 and NF-Y in human cells (Roder et al, 1999;Lim and Chang, 2009). In the human genome, CCAAT and GC boxes are observed to have a high tendency to co-occur in regions 2150/150 bp from transcription start sites (Benner et al, 2013). In addition, NF-Y has genome-wide partnerships with Sp1, and the distances between the cis-acting elements are conversed (Dolfini et al, 2016).…”