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The role of chromatin accessibility in directing the widespread, overlapping patterns of Drosophila transcription factor binding

Journal Article · · GenomeBiology.com
 [1];  [2];  [2];  [3];  [2];  [4]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division; Univ. of California, Berkeley, CA (United States). Howard Hughes Medical Inst.; DOE/OSTI
  2. Univ. of Washington, Seattle, WA (United States). Dept. of Genome Sciences
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division; Univ. of California, Berkeley, CA (United States). Howard Hughes Medical Inst.; Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division

Background: In Drosophila embryos, many biochemically and functionally unrelated transcription factors bind quantitatively to highly overlapping sets of genomic regions, with much of the lowest levels of binding being incidental, non-functional interactions on DNA. The primary biochemical mechanisms that drive these genomewide occupancy patterns have yet to be established. Results: Here we use data resulting from the DNaseI digestion of isolated embryo nuclei to provide a biophysical measure of the degree to which proteins can access different regions of the genome. We show that the in vivo binding patterns of 21 developmental regulators are quantitatively correlated with DNA accessibility in chromatin. Furthermore, we find that levels of factor occupancy in vivo correlate much more with the degree of chromatin accessibility than with occupancy predicted from in vitro affinity measurements using purified protein and naked DNA. Within accessible regions, however, the intrinsic affinity of the factor for DNA does play a role in determining net occupancy, with even weak affinity recognition sites contributing. Finally, we show that programmed changes in chromatin accessibility between different developmental stages correlate with quantitative alterations in factor binding. Conclusions: Based on these and other results, we propose a general mechanism to explain the widespread, overlapping DNA binding by animal transcription factors. In this view, transcription factors are expressed at sufficiently high concentrations in cells such that they can occupy their recognition sequences in highly accessible chromatin without the aid of physical cooperative interactions with other proteins, leading to highly overlapping, graded binding of unrelated factors.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1626737
Journal Information:
GenomeBiology.com, Journal Name: GenomeBiology.com Journal Issue: 4 Vol. 12; ISSN 1465-6906
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English

References (107)

Architectural variations of inducible eukaryotic promoters: Preset and remodeling chromatin structures journal March 1994
Comparison of protein binding to DNA in vivo and in vitro: defining an effective intracellular target. journal December 1995
Transcription factor access to promoter elements journal January 2007
Molecular Integration of Inductive and Mesoderm-Intrinsic Inputs Governs even-skipped Enhancer Activity in a Subset of Pericardial and Dorsal Muscle Progenitors journal October 2001
Identification of regulatory regions which confer muscle-specific gene expression journal April 1998
Computer-assisted identification of cell cycle-related genes: new targets for E2F transcription factors journal May 2001
Molecular mechanisms of cell-type determination in budding yeast journal October 1995
Nucleosome Retention and the Stochastic Nature of Promoter Chromatin Remodeling for Transcription journal May 2008
Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells journal June 2008
Motif-Blind, Genome-Wide Discovery of cis-Regulatory Modules in Drosophila and Mouse journal October 2009
CCCTC-Binding Factor and the Transcription Factor T-bet Orchestrate T Helper 1 Cell-Specific Structure and Function at the Interferon-γ Locus journal October 2009
Different gene regulation strategies revealed by analysis of binding motifs journal October 2009
Chromatin Unfolds journal July 1996
Eukaryotic Transcription: An Interlaced Network of Transcription Factors and Chromatin-Modifying Machines journal February 1998
Evidence for two modes of cooperative DNA binding in vivo that do not involve direct protein–protein interactions journal April 1998
The SWI-SNF complex: a chromatin remodeling machine? journal April 1995
Nucleosomal Context of Binding Sites Influences Transcription Factor Binding Affinity and Gene Regulation journal December 2009
Molecular biology: Anatomy of hypersensitive sites journal May 1984
Transcriptional activation by recruitment journal April 1997
A self-organizing system of repressor gradients establishes segmental complexity in Drosophila journal December 2003
The complex language of chromatin regulation during transcription journal May 2007
Histone modifications at human enhancers reflect global cell-type-specific gene expression journal March 2009
The logic of chromatin architecture and remodelling at promoters journal September 2009
An oestrogen-receptor-α-bound human chromatin interactome journal November 2009
Chromatin accessibility pre-determines glucocorticoid receptor binding patterns journal January 2011
Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing journal June 2007
Hotspots of transcription factor colocalization in the genome of Drosophila melanogaster journal July 2006
Gene regulatory networks and embryonic specification journal April 2008
Nucleosome-mediated cooperativity between transcription factors journal December 2010
Non-specific DNA Binding of Genome Regulating Proteins as a Biological Control Mechanism: 1. The lac Operon: Equilibrium Aspects journal December 1974
Genome-wide histone acetylation data improve prediction of mammalian transcription factor binding sites journal July 2010
The Effects of Selection Against Spurious Transcription Factor Binding Sites journal April 2003
A computational genomics approach to the identification of gene networks journal September 1997
REDfly 2.0: an integrated database of cis-regulatory modules and transcription factor binding sites in Drosophila journal December 2007
MEME SUITE: tools for motif discovery and searching journal May 2009
Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo journal February 2007
Genomic profiling and expression studies reveal both positive and negative activities for the Drosophila Myb MuvB/dREAM complex in proliferating cells journal November 2007
Two homeo domain proteins bind with similar specificity to a wide range of DNA sites in Drosophila embryos. journal July 1994
An ensemble model of competitive multi-factor binding of the genome journal August 2009
Integrating multiple evidence sources to predict transcription factor binding in the human genome journal March 2010
Unbiased location analysis of E2F1-binding sites suggests a widespread role for E2F1 in the human genome journal May 2006
Whole-genome comparison of Leu3 binding in vitro and in vivo reveals the importance of nucleosome occupancy in target site selection journal October 2006
Transcription factor loading on the MMTV promoter: a bimodal mechanism for promoter activation journal March 1992
Binding of disparate transcriptional activators to nucleosomal DNA is inherently cooperative journal March 1995
Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura journal January 2004
The eve stripe 2 enhancer employs multiple modes of transcriptional synergy journal January 1996
Transcriptional Control in the Segmentation Gene Network of Drosophila journal August 2004
A Nucleosome-Guided Map of Transcription Factor Binding Sites in Yeast journal November 2007
Probabilistic Inference of Transcription Factor Binding from Multiple Data Sources journal March 2008
Functional Targets of the Monogenic Diabetes Transcription Factors HNF-1  and HNF-4  Are Highly Conserved Between Mice and Humans journal February 2009
TGF-β Family Signal Transduction in Drosophila Development: From Mad to Smads journal June 1999
A Model for the Cooperative Binding of Eukaryotic Regulatory Proteins to Nucleosomal Target Sites journal May 1996
The general affinity of lac repressor for E. coli DNA: Implications for gene regulation in procaryotes and eucaryotes journal February 1975
Virus induction of human IFNβ gene expression requires the assembly of an enhanceosome journal December 1995
Molecular mechanisms of cell-type determination in budding yeast journal October 1995
Chromatin Unfolds journal July 1996
Eukaryotic Transcription: An Interlaced Network of Transcription Factors and Chromatin-Modifying Machines journal February 1998
Evidence for two modes of cooperative DNA binding in vivo that do not involve direct protein–protein interactions journal April 1998
The SWI-SNF complex: a chromatin remodeling machine? journal April 1995
Specific Gain- and Loss-of-Function Phenotypes Induced by Satellite-Specific DNA-Binding Drugs Fed to Drosophila melanogaster journal November 2000
Recognition of Specific DNA Sequences journal November 2001
Nucleosomal Context of Binding Sites Influences Transcription Factor Binding Affinity and Gene Regulation journal December 2009
Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells journal September 2005
The Role of Chromatin during Transcription journal February 2007
High-Resolution Mapping and Characterization of Open Chromatin across the Genome journal January 2008
A RSC/Nucleosome Complex Determines Chromatin Architecture and Facilitates Activator Binding journal April 2010
Genome-wide MyoD Binding in Skeletal Muscle Cells: A Potential for Broad Cellular Reprogramming journal April 2010
Relationships between p63 Binding, DNA Sequence, Transcription Activity, and Biological Function in Human Cells journal November 2006
Interaction of the Glucocorticoid Receptor with the Chromatin Landscape journal March 2008
The 5′ ends of Drosophila heat shock genes in chromatin are hypersensitive to DNase I journal August 1980
Two protein-binding sites in chromatin implicated in the activation of heat-shock genes journal May 1984
Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF journal January 2001
Controlling the double helix journal January 2003
Combinatorial binding predicts spatio-temporal cis-regulatory activity journal November 2009
Global mapping of protein-DNA interactions in vivo by digital genomic footprinting journal March 2009
Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays journal June 2006
Nucleosome destabilization in the epigenetic regulation of gene expression journal January 2008
Global regulatory logic for specification of an embryonic cell lineage journal April 2008
ChIP-Seq of transcription factors predicts absolute and differential gene expression in embryonic stem cells journal December 2009
Mapping accessible chromatin regions using Sono-Seq journal August 2009
Transcriptional regulatory cascades in development: Initial rates, not steady state, determine network kinetics journal July 2003
DNA binding specificity of two homeodomain proteins in vitro and in Drosophila embryos. journal April 1996
Chromatin-dependent Cooperativity between Site-specific Transcription Factors in Vivo journal March 2007
Functional Sequestration of Transcription Factor Activity by Repetitive DNA journal May 2007
Predicting functional transcription factor binding through alignment-free and affinity-based analysis of orthologous promoter sequences journal July 2008
A comparison of invivo and invitro DNA-binding specificities suggests a new model for homeoprotein DNA binding in Drosophila embryos journal March 1999
Accessibility of transcriptionally inactive genes is specifically reduced at homeoprotein-DNA binding sites in Drosophila journal July 2000
The specificity of protein-DNA crosslinking by formaldehyde: in vitro and in Drosophila embryos journal January 2000
High-throughput chromatin information enables accurate tissue-specific prediction of transcription factor binding sites journal November 2008
Regulation of POU genes by castor and hunchback establishes layered compartments in the Drosophila CNS journal January 1998
A core transcriptional network for early mesoderm development in Drosophila melanogaster journal February 2007
Expression, modification, and localization of the fushi tarazu protein in Drosophila embryos. journal August 1988
Facilitated binding of GAL4 and heat shock factor to nucleosomal templates: differential function of DNA-binding domains. journal July 1991
Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers journal April 2010
Genome-Wide Mapping of in Vivo Protein-DNA Interactions journal June 2007
Collaborative Competition Mechanism for Gene Activation In Vivo journal March 2003
Global Nature of Dynamic Protein-Chromatin Interactions In Vivo: Three-Dimensional Genome Scanning and Dynamic Interaction Networks of Chromatin Proteins journal July 2004
Nuclease Hypersensitive Sites in Chromatin journal June 1988
Quantifying similarity between motifs journal January 2007
Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions journal January 2009
Genome-wide prediction of transcription factor binding sites using an integrated model journal January 2010
Stepwise formation of a SMAD activity gradient during dorsal-ventral patterning of the Drosophila embryo journal December 2003
Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm journal February 2008
Binding Site Turnover Produces Pervasive Quantitative Changes in Transcription Factor Binding between Closely Related Drosophila Species journal March 2010
Quantitative Models of the Mechanisms That Control Genome-Wide Patterns of Transcription Factor Binding during Early Drosophila Development journal February 2011
Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project text January 2007
Whole-genome comparison of Leu3 binding in vitro and in vivo reveals the importance of nucleosome occupancy in target site selection text January 2006

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Link of Zygotic Genome Activation and Cell Cycle Control book January 2017
Distinct mechanisms of transcriptional pausing orchestrated by GAGA factor and M1BP, a novel transcription factor journal May 2013
An integrated encyclopedia of DNA elements in the human genome journal September 2012
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Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal journal October 2014
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ChIPulate: A comprehensive ChIP-seq simulation pipeline journal March 2019
Zelda Binding in the Early Drosophila melanogaster Embryo Marks Regions Subsequently Activated at the Maternal-to-Zygotic Transition journal October 2011
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