title: Genome-wide analysis reveals positional-nucleosome-oriented binding pattern of pioneer factor FOXA1.
abstract: The compaction of nucleosomal structures creates a barrier for DNA-binding transcription factors (TFs) to access their cognate cis-regulatory elements. Pioneer factors (PFs) such as FOXA1 are able to directly access these cis-targets within compact chromatin. However, how these PFs interplay with nucleosomes remains to be elucidated, and is critical for us to understand the underlying mechanism of gene regulation. Here, we have conducted a computational analysis on a strand-specific paired-end ChIP-exo (termed as ChIP-ePENS) data of FOXA1 in LNCaP cells by our novel algorithm ePEST. We find that FOXA1 chromatin binding occurs via four distinct border modes (or footprint boundary patterns), with a preferential footprint boundary patterns relative to FOXA1 motif orientation. In addition, from this analysis three fundamental nucleotide positions (oG, oS and oH) emerged as major determinants for blocking exo-digestion and forming these four distinct border modes. By integrating histone MNase-seq data, we found an astonishingly consistent, 'well-positioned' configuration occurs between FOXA1 motifs and dyads of nucleosomes genome-wide. We further performed ChIP-seq of eight chromatin remodelers and found an increased occupancy of these remodelers on FOXA1 motifs for all four border modes (or footprint boundary patterns), indicating the full occupancy of FOXA1 complex on the three blocking sites (oG, oS and oH) likely produces an active regulatory status with well-positioned phasing for protein binding events. Together, our results suggest a positional-nucleosome-oriented accessing model for PFs seeking target motifs, in which FOXA1 can examine each underlying DNA nucleotide and is able to sense all potential motifs regardless of whether they face inward or outward from histone octamers along the DNA helix axis.
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX 78229, USA.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, OH 43210, USA Comprehensive Cancer Center, The Ohio State University College of Medicine, OH 43210, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, OH 43210, USA Comprehensive Cancer Center, The Ohio State University College of Medicine, OH 43210, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sunkel
authors.affiliation: MLRS Department, University of Vermont, VT 05405, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Frietze
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX 78229, USA.
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, OH 43210, USA Comprehensive Cancer Center, The Ohio State University College of Medicine, OH 43210, USA qianben.wang@osumc.edu.
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX 78229, USA jinv@uthscsa.edu.
authors.forename: Victor X
authors.initials: VX
authors.lastname: Jin
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D015894:Genome, Human; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009707:Nucleosomes / Q000378:metabolism*; D059372:Nucleotide Motifs / Q000235:genetics; D011485:Protein Binding; D011499:Protein Processing, Post-Translational
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D009707:Nucleosomes