Dynamic Exchange at Regulatory Elements during Chromatin Remodeling Underlies Assisted Loading Mechanism

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.

[1]  G. Hager,et al.  ATP-Dependent Mobilization of the Glucocorticoid Receptor during Chromatin Remodeling , 2002, Molecular and Cellular Biology.

[2]  B. Katzenellenbogen,et al.  Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  F. Holstege,et al.  Distinct promoter dynamics of the basal transcription factor TBP across the yeast genome , 2009, Nature Structural &Molecular Biology.

[4]  E. Segal,et al.  Predicting expression patterns from regulatory sequence in Drosophila segmentation , 2008, Nature.

[5]  P. Chambon,et al.  Three amino acids of the oestrogen receptor are essential to its ability to distinguish an oestrogen from a glucocorticoid-responsive element , 1989, Nature.

[6]  J. Eeckhoute,et al.  Unique ERalpha cistromes control cell type-specific gene regulation. , 2008, Molecular endocrinology.

[7]  J. Carroll,et al.  Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state , 2007, Nature Reviews Cancer.

[8]  G. Hager,et al.  Using inducible vectors to study intracellular trafficking of GFP-tagged steroid/nuclear receptors in living cells. , 1999, Methods.

[9]  S. Batzoglou,et al.  Genome-Wide Analysis of Transcription Factor Binding Sites Based on ChIP-Seq Data , 2008, Nature Methods.

[10]  G. Hager,et al.  Rapid periodic binding and displacement of the glucocorticoid receptor during chromatin remodeling. , 2004, Molecular cell.

[11]  A. Hartemink,et al.  An ensemble model of competitive multi-factor binding of the genome. , 2009, Genome research.

[12]  J. Stamatoyannopoulos,et al.  Interaction of the Glucocorticoid Receptor with the Chromatin Landscape , 2008, Molecular cell.

[13]  E. O’Shea,et al.  A quantitative model of transcription factor–activated gene expression , 2008, Nature Structural &Molecular Biology.

[14]  G. Hager,et al.  Modulation of enhancer activity by the hormone responsive regulatory element from mouse mammary tumor virus. , 1984, The EMBO journal.

[15]  T. Kodadek,et al.  Proteolytic turnover of the Gal4 transcription factor is not required for function in vivo , 2006, Nature.

[16]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[17]  E. Soeth,et al.  Inhibition of MMTV transcription by HDAC inhibitors occurs independent of changes in chromatin remodeling and increased histone acetylation , 2003, Oncogene.

[18]  Alexander van Oudenaarden,et al.  Stochastic Gene Expression: from Single Molecules to the Proteome This Review Comes from a Themed Issue on Chromosomes and Expression Mechanisms Edited Measuring Noise Mrna Fluctuations , 2022 .

[19]  P. Chambon,et al.  Steroid hormone receptors compete for factors that mediate their enhancer function , 1989, Cell.

[20]  J. McNally,et al.  The glucocorticoid receptor: rapid exchange with regulatory sites in living cells. , 2000, Science.

[21]  T. Misteli,et al.  Transcription dynamics. , 2009, Molecular cell.

[22]  Ty C. Voss,et al.  Combinatorial probabilistic chromatin interactions produce transcriptional heterogeneity , 2009, Journal of Cell Science.

[23]  William Stafford Noble,et al.  Global mapping of protein-DNA interactions in vivo by digital genomic footprinting , 2009, Nature Methods.

[24]  X. Darzacq,et al.  In vivo dynamics of RNA polymerase II transcription , 2007, Nature Structural &Molecular Biology.

[25]  Ty C. Voss,et al.  Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription , 2009, Nature Cell Biology.

[26]  James G McNally,et al.  Dynamic behavior of transcription factors on a natural promoter in living cells , 2002, EMBO reports.

[27]  J. Stamatoyannopoulos,et al.  Chromatin accessibility pre-determines glucocorticoid receptor binding patterns , 2011, Nature Genetics.

[28]  William Stafford Noble,et al.  Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays , 2006, Nature Methods.

[29]  Roger D. Kornberg,et al.  Nucleosome Retention and the Stochastic Nature of Promoter Chromatin Remodeling for Transcription , 2008, Cell.

[30]  A. Mortazavi,et al.  Genome-Wide Mapping of in Vivo Protein-DNA Interactions , 2007, Science.

[31]  Allen D. Delaney,et al.  Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing , 2007, Nature Methods.

[32]  N. D. Clarke,et al.  Explicit equilibrium modeling of transcription-factor binding and gene regulation , 2005, Genome Biology.

[33]  Clifford A. Meyer,et al.  Nucleosome Dynamics Define Transcriptional Enhancers , 2010, Nature Genetics.

[34]  Frank R. Lin,et al.  Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. , 2002, Molecular cell.

[35]  J. Cann.  Phenomenological theory of gel electrophoresis of protein-nucleic acid complexes. , 1989, The Journal of biological chemistry.

[36]  Cem Elbi,et al.  Protein dynamics in the nuclear compartment. , 2002, Current opinion in genetics & development.

[37]  Raja Jothi,et al.  Genome-wide identification of in vivo protein–DNA binding sites from ChIP-Seq data , 2008, Nucleic acids research.

[38]  O. Wrange,et al.  Assays for transcription factors access to nucleosomal DNA. , 1997, Methods.

[39]  Adam T. Szafran,et al.  Estrogen-receptor-α exchange and chromatin dynamics are ligand- and domain-dependent , 2006, Journal of Cell Science.

[40]  K. Yamamoto,et al.  Sequence-specific binding of glucocorticoid receptor to MTV DNA at sites within and upstream of the transcribed region , 1983, Cell.