Dataset Information

Decoding the Inversion Symmetry Underlying Transcription Factor DNA-Binding Specificity and Functionality in the Genome.

ABSTRACT: Understanding why a transcription factor (TF) binds to a specific DNA element in the genome and whether that binding event affects transcriptional output remains a great challenge. In this study, we demonstrate that TF binding in the genome follows inversion symmetry (IS). In addition, the specific DNA elements where TFs bind in the genome are determined by internal IS within the DNA element. These DNA-binding rules quantitatively define how TFs select the appropriate regulatory targets from a large number of similar DNA elements in the genome to elicit specific transcriptional and cellular responses. Importantly, we also demonstrate that these DNA-binding rules extend to DNA elements that do not support transcriptional activity. That is, the DNA-binding rules are obeyed, but the retention time of the TF at these non-functional DNA elements is not long enough to initiate and/or maintain transcription. We further demonstrate that IS is universal within the genome. Thus, IS is the DNA code that TFs use to interact with the genome and dictates (in conjunction with known DNA sequence constraints) which of those interactions are functionally active.

SUBMITTER: Coons LA

PROVIDER: S-EPMC6542189 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Decoding the Inversion Symmetry Underlying Transcription Factor DNA-Binding Specificity and Functionality in the Genome.

Coons Laurel A LA Burkholder Adam B AB Hewitt Sylvia C SC McDonnell Donald P DP Korach Kenneth S KS

iScience 20190406

Understanding why a transcription factor (TF) binds to a specific DNA element in the genome and whether that binding event affects transcriptional output remains a great challenge. In this study, we demonstrate that TF binding in the genome follows inversion symmetry (IS). In addition, the specific DNA elements where TFs bind in the genome are determined by internal IS within the DNA element. These DNA-binding rules quantitatively define how TFs select the appropriate regulatory targets from a l ...[more]

PMID: 31152742

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Project description:To elucidate how genomic sequences build transcriptional control networks, we need to understand the connection between DNA sequence and transcription factor binding and function. Binding predictions based solely on consensus predictions are limited, because a single factor can use degenerate sequence motifs and because related transcription factors often prefer identical sequences. The ETS family transcription factor, ETS1, exemplifies these challenges. Unexpected, redundant occupancy of ETS1 and other ETS proteins is observed at promoters of housekeeping genes in T cells due to common sequence preferences and the presence of strong consensus motifs. However, ETS1 exhibits a specific function in T cell activation; thus, unique transcriptional targets are predicted. To uncover the sequence motifs that mediate specific functions of ETS1, a genome-wide approach, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), identified both promoter and enhancer binding events in Jurkat T cells. A comparison with DNase I sensitivity both validated the dataset and also improved accuracy. Redundant occupancy of ETS1 with the ETS protein GABPA occurred primarily in promoters of housekeeping genes, whereas ETS1 specific occupancy occurred in the enhancers of T cell-specific genes. Two routes to ETS1 specificity were identified: an intrinsic preference of ETS1 for a variant of the ETS family consensus sequence and the presence of a composite sequence that can support cooperative binding with a RUNX transcription factor. Genome-wide occupancy of RUNX factors corroborated the importance of this partnership. Furthermore, genome-wide occupancy of co-activator CBP indicated tight co-localization with ETS1 at specific enhancers, but not redundant promoters. The distinct sequences associated with redundant versus specific ETS1 occupancy were predictive of promoter or enhancer location and the ontology of nearby genes. These findings demonstrate that diversity of DNA binding motifs may enable variable transcription factor function at different genomic sites.

Dataset Information

Decoding the Inversion Symmetry Underlying Transcription Factor DNA-Binding Specificity and Functionality in the Genome.

Publications

Decoding the Inversion Symmetry Underlying Transcription Factor DNA-Binding Specificity and Functionality in the Genome.

Similar Datasets

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