Prediction of cooperative homeodomain DNA binding sites from high-throughput-SELEX data.

Autor:	Cain B; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45221, USA.; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7007, Cincinnati, OH 45229, USA., Webb J; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Yuan Z; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Cheung D; Graduate Program in Molecular and Developmental Biology, Ci ncinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA., Lim HW; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Kovall RA; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Weirauch MT; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.; Divisions of Human Genetics, Biomedical Informatics and Developmental Biology, Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Gebelein B; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7007, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2023 Jul 07; Vol. 51 (12), pp. 6055-6072.
DOI:	10.1093/nar/gkad318
Abstrakt:	Homeodomain proteins constitute one of the largest families of metazoan transcription factors. Genetic studies have demonstrated that homeodomain proteins regulate many developmental processes. Yet, biochemical data reveal that most bind highly similar DNA sequences. Defining how homeodomain proteins achieve DNA binding specificity has therefore been a long-standing goal. Here, we developed a novel computational approach to predict cooperative dimeric binding of homeodomain proteins using High-Throughput (HT) SELEX data. Importantly, we found that 15 of 88 homeodomain factors form cooperative homodimer complexes on DNA sites with precise spacing requirements. Approximately one third of the paired-like homeodomain proteins cooperatively bind palindromic sequences spaced 3 bp apart, whereas other homeodomain proteins cooperatively bind sites with distinct orientation and spacing requirements. Combining structural models of a paired-like factor with our cooperativity predictions identified key amino acid differences that help differentiate between cooperative and non-cooperative factors. Finally, we confirmed predicted cooperative dimer sites in vivo using available genomic data for a subset of factors. These findings demonstrate how HT-SELEX data can be computationally mined to predict cooperativity. In addition, the binding site spacing requirements of select homeodomain proteins provide a mechanism by which seemingly similar AT-rich DNA sequences can preferentially recruit specific homeodomain factors. (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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