title: Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism.
abstract: The glucocorticoid receptor (GR), like other eukaryotic transcription factors, regulates gene expression by interacting with chromatinized DNA response elements. Photobleaching experiments in living cells indicate that receptors transiently interact with DNA on the time scale of seconds and predict that the response elements may be sparsely occupied on average. Here, we show that the binding of one receptor at the glucocorticoid response element (GRE) does not reduce the steady-state binding of another receptor variant to the same GRE. Mathematical simulations reproduce this noncompetitive state using short GR/GRE residency times and relatively long times between DNA binding events. At many genomic sites where GR binding causes increased chromatin accessibility, concurrent steady-state binding levels for the variant receptor are actually increased, a phenomenon termed assisted loading. Temporally sparse transcription factor-DNA interactions induce local chromatin reorganization, resulting in transient access for binding of secondary regulatory factors.
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, Building 41, B602, 41 Library Drive, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ty C
authors.initials: TC
authors.lastname: Voss
authors.forename: R Louis
authors.initials: RL
authors.lastname: Schiltz
authors.forename: Myong-Hee
authors.initials: MH
authors.lastname: Sung
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Simon C
authors.initials: SC
authors.lastname: Biddie
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Johnson
authors.forename: Tina B
authors.initials: TB
authors.lastname: Miranda
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008954:Models, Biological; D009010:Monte Carlo Method; D009707:Nucleosomes / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D009707:Nucleosomes; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D000255:Adenosine Triphosphate