title: Prediction of DNA binding motifs from 3D models of transcription factors; identifying TLX3 regulated genes.
abstract: Proper cell functioning depends on the precise spatio-temporal expression of its genetic material. Gene expression is controlled to a great extent by sequence-specific transcription factors (TFs). Our current knowledge on where and how TFs bind and associate to regulate gene expression is incomplete. A structure-based computational algorithm (TF2DNA) is developed to identify binding specificities of TFs. The method constructs homology models of TFs bound to DNA and assesses the relative binding affinity for all possible DNA sequences using a knowledge-based potential, after optimization in a molecular mechanics force field. TF2DNA predictions were benchmarked against experimentally determined binding motifs. Success rates range from 45% to 81% and primarily depend on the sequence identity of aligned target sequences and template structures, TF2DNA was used to predict 1321 motifs for 1825 putative human TF proteins, facilitating the reconstruction of most of the human gene regulatory network. As an illustration, the predicted DNA binding site for the poorly characterized T-cell leukemia homeobox 3 (TLX3) TF was confirmed with gel shift assay experiments. TLX3 motif searches in human promoter regions identified a group of genes enriched in functions relating to hematopoiesis, tissue morphology, endocrine system and connective tissue development and function.
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Pujato
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA Macromolecular Therapeutics Development, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Kieken
authors.affiliation: Molecular Neuroscience Laboratory, Geisinger Clinic, 100 North Academy Avenue, Danville, PA 17822, USA.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Skiles
authors.affiliation: Molecular Neuroscience Laboratory, Geisinger Clinic, 100 North Academy Avenue, Danville, PA 17822, USA.
authors.forename: Nikos
authors.initials: N
authors.lastname: Tapinos
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA andras.fiser@einstein.yu.edu.
authors.forename: Andras
authors.initials: A
authors.lastname: Fiser
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C489494:TLX3 protein, human; D014157:Transcription Factors; D004247:DNA