Determinants of Cell- and Gene-Specific Transcriptional Regulation by the Glucocorticoid Receptor

The glucocorticoid receptor (GR) associates with glucocorticoid response elements (GREs) and regulates selective gene transcription in a cell-specific manner. Native GREs are typically thought to be composite elements that recruit GR as well as other regulatory factors into functional complexes. We assessed whether GR occupancy is commonly a limiting determinant of GRE function as well as the extent to which core GR binding sequences and GRE architecture are conserved at functional loci. We surveyed 100-kb regions surrounding each of 548 known or potentially glucocorticoid-responsive genes in A549 human lung cells for GR-occupied GREs. We found that GR was bound in A549 cells predominately near genes responsive to glucocorticoids in those cells and not at genes regulated by GR in other cells. The GREs were positionally conserved at each responsive gene but across the set of responsive genes were distributed equally upstream and downstream of the transcription start sites, with 63% of them >10 kb from those sites. Strikingly, although the core GR binding sequences across the set of GREs varied extensively around a consensus, the precise sequence at an individual GRE was conserved across four mammalian species. Similarly, sequences flanking the core GR binding sites also varied among GREs but were conserved at individual GREs. We conclude that GR occupancy is a primary determinant of glucocorticoid responsiveness in A549 cells and that core GR binding sequences as well as GRE architecture likely harbor gene-specific regulatory information.

[1]  Clifford A. Meyer,et al.  Genome-wide analysis of estrogen receptor binding sites , 2006, Nature Genetics.

[2]  Richard Axel,et al.  Interchromosomal Interactions and Olfactory Receptor Choice , 2006, Cell.

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

[4]  Mark Bieda,et al.  Unbiased location analysis of E2F1-binding sites suggests a widespread role for E2F1 in the human genome. , 2006, Genome research.

[5]  Sin Lam Tan,et al.  Mice and Men: Their Promoter Properties , 2006, PLoS genetics.

[6]  K. Yamamoto,et al.  Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity. , 2006, Genes & development.

[7]  Jeffrey A. Magee,et al.  Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element. , 2006, Endocrinology.

[8]  Mark Gerstein,et al.  Global changes in STAT target selection and transcription regulation upon interferon treatments. , 2005, Genes & development.

[9]  Céline Lefebvre,et al.  From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Jonathan Schug,et al.  Glucocorticoid Receptor-Dependent Gene Regulatory Networks , 2005, PLoS genetics.

[11]  Clifford A. Meyer,et al.  Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1 , 2005, Cell.

[12]  C. Geserick,et al.  The role of DNA response elements as allosteric modulators of steroid receptor function , 2005, Molecular and Cellular Endocrinology.

[13]  Jeffrey N Miner,et al.  The search for safer glucocorticoid receptor ligands. , 2005, Endocrine reviews.

[14]  K. Yamamoto,et al.  The glucocorticoid receptor blocks P-TEFb recruitment by NFkappaB to effect promoter-specific transcriptional repression. , 2005, Genes & development.

[15]  K. Yamamoto,et al.  Chromatin immunoprecipitation (ChIP) scanning identifies primary glucocorticoid receptor target genes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  David Baltimore,et al.  One Nucleotide in a κB Site Can Determine Cofactor Specificity for NF-κB Dimers , 2004, Cell.

[17]  D. Chalbos,et al.  Mechanisms underlying differential expression of interleukin-8 in breast cancer cells , 2004, Oncogene.

[18]  Peter Walter,et al.  Gcn4p and Novel Upstream Activating Sequences Regulate Targets of the Unfolded Protein Response , 2004, PLoS biology.

[19]  G. Crooks,et al.  WebLogo: a sequence logo generator. , 2004, Genome research.

[20]  E. Birney,et al.  Comparison of human chromosome 21 conserved nongenic sequences (CNGs) with the mouse and dog genomes shows that their selective constraint is independent of their genic environment. , 2004, Genome research.

[21]  W. Vedeckis,et al.  Steroid-responsive sequences in the human glucocorticoid receptor gene 1A promoter. , 2004, Molecular endocrinology.

[22]  A. Hoffmann,et al.  One nucleotide in a kappaB site can determine cofactor specificity for NF-kappaB dimers. , 2004, Cell.

[23]  Patrick Yau,et al.  High-throughput screening of chromatin immunoprecipitates using CpG-island microarrays. , 2004, Methods in enzymology.

[24]  Kenta Nakai,et al.  BTSS, DataBase of Transcriptional Start Sites: progress report 2004 , 2004, Nucleic Acids Res..

[25]  K. Yamamoto,et al.  Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Thomas E. Royce,et al.  Distribution of NF-κB-binding sites across human chromosome 22 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Alexander E. Kel,et al.  TRANSFAC®: transcriptional regulation, from patterns to profiles , 2003, Nucleic Acids Res..

[28]  Mark Gerstein,et al.  Distribution of NF-kappaB-binding sites across human chromosome 22. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  K. Yamamoto,et al.  Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. V. Jongeneel,et al.  Numerous potentially functional but non-genic conserved sequences on human chromosome 21 , 2002, Nature.

[31]  O. Dittrich‐Breiholz,et al.  Multiple control of interleukin‐8 gene expression , 2002, Journal of leukocyte biology.

[32]  Biaoyang Lin,et al.  The program of androgen-responsive genes in neoplastic prostate epithelium , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Eric D Siggia,et al.  Identification of the binding sites of regulatory proteins in bacterial genomes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Robert Tibshirani,et al.  Transcriptional programs activated by exposure of human prostate cancer cells to androgen , 2002, Genome Biology.

[35]  W. Mitch,et al.  Ubiquitin (UbC) Expression in Muscle Cells Is Increased by Glucocorticoids through a Mechanism Involving Sp1 and MEK1* , 2002, The Journal of Biological Chemistry.

[36]  M. Shannon,et al.  Chromatin Remodeling, Measured by a Novel Real-Time Polymerase Chain Reaction Assay, Across the Proximal Promoter Region of the IL-2 Gene , 2001, The Journal of Immunology.

[37]  Douglas L. Brutlag,et al.  BioProspector: Discovering Conserved DNA Motifs in Upstream Regulatory Regions of Co-Expressed Genes , 2000, Pacific Symposium on Biocomputing.

[38]  M. Rosenfeld,et al.  Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specification. , 2000, Science.

[39]  H. Bussemaker,et al.  Building a dictionary for genomes: identification of presumptive regulatory sites by statistical analysis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Hao Li,et al.  Regulatory Element Detection Using a Probabilistic Segmentation Model , 2000, ISMB.

[41]  A. Jobe,et al.  Lung development and function in preterm infants in the surfactant treatment era. , 2000, Annual review of physiology.

[42]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[43]  M. Groudine,et al.  Looping versus linking: toward a model for long-distance gene activation. , 1999, Genes & development.

[44]  J. Stokes,et al.  Glucocorticoid Induction of Epithelial Sodium Channel Expression in Lung and Renal Epithelia Occurs via trans-Activation of a Hormone Response Element in the 5′-Flanking Region of the Human Epithelial Sodium Channel α Subunit Gene* , 1999, The Journal of Biological Chemistry.

[45]  J. Wang,et al.  The phosphoenolpyruvate carboxykinase gene glucocorticoid response unit: identification of the functional domains of accessory factors HNF3 beta (hepatic nuclear factor-3 beta) and HNF4 and the necessity of proper alignment of their cognate binding sites. , 1999, Molecular endocrinology.

[46]  Zohar Yakhini,et al.  Clustering gene expression patterns , 1999, J. Comput. Biol..

[47]  Jeffrey A. Lefstin,et al.  Allosteric effects of DNA on transcriptional regulators , 1998, Nature.

[48]  K. Yamamoto,et al.  Building transcriptional regulatory complexes: signals and surfaces. , 1998, Cold Spring Harbor symposia on quantitative biology.

[49]  J. Thompson,et al.  Using CLUSTAL for multiple sequence alignments. , 1996, Methods in enzymology.

[50]  Yamamoto Kr.  Multilayered control of intracellular receptor function. , 1995 .

[51]  K. Yamamoto.  Multilayered control of intracellular receptor function. , 1995, Harvey lectures.

[52]  Jeffrey A. Lefstin,et al.  Influence of a steroid receptor DNA-binding domain on transcriptional regulatory functions. , 1994, Genes & development.

[53]  K. Yamamoto,et al.  Analysis of the DNA-binding affinity, sequence specificity and context dependence of the glucocorticoid receptor zinc finger region. , 1994, Journal of molecular biology.

[54]  M. Parker,et al.  A consensus DNA-binding site for the androgen receptor. , 1992, Molecular endocrinology.

[55]  K. Yamamoto,et al.  Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA , 2003, Nature.

[56]  C. Hutchison,et al.  Structural determinants of a glucocorticoid receptor recognition element. , 1990, Molecular endocrinology.

[57]  K. Yamamoto.  A Conceptual View of Transcriptional Regulation , 1989 .

[58]  M. Schauer,et al.  DNA regulatory elements for steroid hormones. , 1989, Journal of steroid biochemistry.

[59]  G. Schütz,et al.  A DNA sequence of 15 base pairs is sufficient to mediate both glucocorticoid and progesterone induction of gene expression. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[60]  B. Gloss,et al.  Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene , 1987, Cell.

[61]  Keith R. Yamamoto,et al.  Reversible and persistent changes in chromatin structure accompany activation of a glucocorticoid-dependent enhancer element , 1984, Cell.

[62]  K. Yamamoto,et al.  DNA sequences bound specifically by glucocorticoid receptor in vitro render a heterologous promoter hormone responsive in vivo , 1983, Cell.