Decoding a signature-based model of transcription cofactor recruitment dictated by cardinal cis-regulatory elements in proximal promoter regions.
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.
The Salk Institute for Biological Studies, La Jolla, California, United States of America.
Christopher
C
Benner
Sergiy
S
Konovalov
Carlos
C
Mackintosh
Kasey R
KR
Hutt
Rieka
R
Stunnenberg
Ivan
I
Garcia-Bassets
D002843:Chromatin / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D003850:Deoxyribonuclease I / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D051266:Nuclear Respiratory Factor 1; D059372:Nucleotide Motifs / Q000235:genetics; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D024363:Transcription Initiation Site
D002843:Chromatin; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D014157:Transcription Factors; D003850:Deoxyribonuclease I