Year: 2024
Type: article
Abstract: Patterns of transcriptional activity are encoded in our genome through regulatory elements such as promoters or enhancers that, paradoxically, contain similar assortments of sequence-specific transcription factor (TF) binding sites 1–3 . Knowledge of how these sequence motifs encode multiple, often overlapping, gene expression programs is central to understanding gene regulation and how mutations in non-coding DNA manifest in disease 4,5 . Here, by studying gene regulation from the perspective of individual transcription start sites (TSSs), using natural genetic variation, perturbation of endogenous TF protein levels and massively parallel analysis of natural and synthetic regulatory elements, we show that the effect of TF binding on transcription initiation is position dependent. Analysing TF-binding-site occurrences relative to the TSS, we identified several motifs with highly preferential positioning. We show that these patterns are a combination of a TF’s distinct functional profiles—many TFs, including canonical activators such as NRF1, NFY and Sp1, activate or repress transcription initiation depending on their precise position relative to the TSS. As such, TFs and their spacing collectively guide the site and frequency of transcription initiation. More broadly, these findings reveal how similar assortments of TF binding sites can generate distinct gene regulatory outcomes depending on their spatial configuration and how DNA sequence polymorphisms may contribute to transcription variation and disease and underscore a critical role for TSS data in decoding the regulatory information of our genome.
Source: Nature
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Funders: National Institutes of Health, University of California, San Diego, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, U.S. National Library of Medicine
Awards: G1032950088, G1225124288, G1476237564, Exploiting Natural Genetic and Organismic Variation to Identify the DNA Motifs Regulating Transcription, G2689462013, Deconvolution of pro- and anti-viral responses to Dengue virus and Zika Virus infections, G297113894, Illumina NovaSeq 6000 Sequencing System, G403864660, G4331485606, Deciphering the contribution of enhancer transcription to enhancer function, G4927841016, G595500114, G598865872, G634779731, G745487158, G7501542120, G9000002805, G9000019377, G9000030219, G9000074399, G9000079683, G9000089620, G9000132884, G9000166923, San Diego Digestive Diseases Research Center, Novel SETD5-based Molecular Mechanisms and Therapeutic Tools to Understand and Revert Neuronal Dysfunction Associated with Intellectual disability and Autism
OpenAlex ID: W4400729643