title: The Pioneer Transcription Factor FoxA Maintains an Accessible Nucleosome Configuration at Enhancers for Tissue-Specific Gene Activation.
abstract: Nuclear DNA wraps around core histones to form nucleosomes, which restricts the binding of transcription factors to gene regulatory sequences. Pioneer transcription factors can bind DNA sites on nucleosomes and initiate gene regulatory events, often leading to the local opening of chromatin. However, the nucleosomal configuration of open chromatin and the basis for its regulation is unclear. We combined low and high levels of micrococcal nuclease (MNase) digestion along with core histone mapping to assess the nucleosomal configuration at enhancers and promoters in mouse liver. We find that MNase-accessible nucleosomes, bound by transcription factors, are retained more at liver-specific enhancers than at promoters and ubiquitous enhancers. The pioneer factor FoxA displaces linker histone H1, thereby keeping enhancer nucleosomes accessible in chromatin and allowing other liver-specific transcription factors to bind and stimulate transcription. Thus, nucleosomes are not exclusively repressive to gene regulation when they are retained with, and exposed by, pioneer factors.
authors.affiliation: Department of Cell and Developmental Biology and Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA.
authors.forename: Makiko
authors.initials: M
authors.lastname: Iwafuchi-Doi
authors.affiliation: Department of Cell and Developmental Biology and Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Donahue
authors.affiliation: Department of Biochemistry and Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Akshay
authors.initials: A
authors.lastname: Kakumanu
authors.affiliation: Department of Cell and Developmental Biology and Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Watts
authors.affiliation: Department of Biochemistry and Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Mahony
authors.affiliation: Department of Biochemistry and Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: B Franklin
authors.initials: BF
authors.lastname: Pugh
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA.
authors.forename: Dolim
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Department of Cell and Developmental Biology and Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA. Electronic address: zaret@upenn.edu.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Zaret
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C496506:Foxa3 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D009707:Nucleosomes; D051543:Hepatocyte Nuclear Factor 3-gamma; D051542:Hepatocyte Nuclear Factor 3-beta