An integrative analysis of TFBS-clustered regions reveals new transcriptional regulation models on the accessible chromatin landscape

DNase I hypersensitive sites (DHSs) define the accessible chromatin landscape and have revolutionised the discovery of distinct cis-regulatory elements in diverse organisms. Here, we report the first comprehensive map of human transcription factor binding site (TFBS)-clustered regions using Gaussian kernel density estimation based on genome-wide mapping of the TFBSs in 133 human cell and tissue types. Approximately 1.6 million distinct TFBS-clustered regions, collectively spanning 27.7% of the human genome, were discovered. The TFBS complexity assigned to each TFBS-clustered region was highly correlated with genomic location, cell selectivity, evolutionary conservation, sequence features and functional roles. An integrative analysis of these regions using ENCODE data revealed transcription factor occupancy, transcriptional activity, histone modification, DNA methylation and chromatin structures that varied based on TFBS complexity. Furthermore, we found that we could recreate lineage-branching relationships by simple clustering of the TFBS-clustered regions from terminally differentiated cells. Based on these findings, a model of transcriptional regulation determined by TFBS complexity is proposed.

• Publication year

  2015

• Venue

  Scientific Reports

• Publication date

  2015-02-16

• Fields of study

  Biology, Medicine, Computer Science

• Identifiers
  DOI 10.1038/srep08465PMID 25682954PMCID 4329551
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Evolutionarily conserved elements in vertebrate , insect , worm , and yeast genomes

  2015cited by this paper
• Architectural proteins CTCF and cohesin have distinct roles in modulating the higher order structure and expression of the CFTR locus

  2014cited by this paper
• Extreme HOT regions are CpG-dense promoters in C. elegans and humans

  2014cited by this paper
• Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster

  2014cited by this paper
• Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells

  2013cited by this paper
• Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation

  2013cited by this paper
• Gene pair signatures in cell type transcriptomes reveal lineage control

  2013cited by this paper
• Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription.

  2013cited by this paper
• Developmental fate and cellular maturity encoded in human regulatory DNA landscapes.

  2013cited by this paper
• C-Terminal Binding Protein (CtBP) Activates the Expression of E-Box Clock Genes with CLOCK/CYCLE in Drosophila

  2013cited by this paper
• The UCSC Genome Browser database: 2014 update

  2013cited by this paper
• Faculty Opinions recommendation of Gene-pair expression signatures reveal lineage control.

  2013cited by this paper
• MethylCRF, an Algorithm for Estimating Absolute Methylation Levels at Single CpG Resolution from Methylation Enrichment and Restriction Enzyme Sequencing Methods

  2013cited by this paper
• Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells

  2013cited by this paper
• Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

  2013cited by this paper
• Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites.

  2013influential reference
• An expansive human regulatory lexicon encoded in transcription factor footprints

  2012cited by this paper
• Noncoding transcription at enhancers: general principles and functional models.

  2012cited by this paper
• GENCODE: The reference human genome annotation for The ENCODE Project

  2012cited by this paper
• A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals.

  2012cited by this paper
• Personal and population genomics of human regulatory variation

  2012cited by this paper
• The accessible chromatin landscape of the human genome

  2012cited by this paper
• Architecture of the human regulatory network derived from ENCODE data

  2012cited by this paper
• Comprehensive Identification and Annotation of Cell Type-Specific and Ubiquitous CTCF-Binding Sites in the Human Genome

  2012cited by this paper
• BEDOPS: high-performance genomic feature operations

  2012influential reference
• Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors

  2012cited by this paper
• HOT regions function as patterned developmental enhancers and have a distinct cis-regulatory signature.

  2012cited by this paper
• An Integrated Encyclopedia of DNA Elements in the Human Genome

  2012cited by this paper
• Chromatin accessibility pre-determines glucocorticoid receptor binding patterns

  2011cited by this paper
• DNA-binding factors shape the mouse methylome at distal regulatory regions

  2011cited by this paper
• A cis-regulatory map of the Drosophila genome

  2011cited by this paper
• Determinants of nucleosome organization in primary human cells

  2011cited by this paper
• Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE

  2010cited by this paper
• A phylogenetically based transcriptome age index mirrors ontogenetic divergence patterns

  2010cited by this paper
• Gene expression divergence recapitulates the developmental hourglass model

  2010cited by this paper
• Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.

  2010cited by this paper
• UniPROBE, update 2011: expanded content and search tools in the online database of protein-binding microarray data on protein–DNA interactions

  2010cited by this paper
• The NIH Roadmap Epigenomics Mapping Consortium

  2010cited by this paper
• Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project

  2010cited by this paper
• Subsampling methods for genomic inference

  2010cited by this paper
• Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions

  2009cited by this paper
• A census of human transcription factors: function, expression and evolution

  2009cited by this paper
• Ultrafast and memory-efficient alignment of short DNA sequences to the human genome

  2009cited by this paper
• Global mapping of protein-DNA interactions in vivo by digital genomic footprinting

  2009cited by this paper
• JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles

  2009cited by this paper
• High-resolution mapping and characterization of open chromatin across the genome.

  2008cited by this paper
• Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources

  2008cited by this paper
• The Insulator Binding Protein CTCF Positions 20 Nucleosomes around Its Binding Sites across the Human Genome

  2008cited by this paper
• Society for Industrial and Applied Mathematics(SIAM)

  2008cited by this paper
• Integration of external signaling pathways with the core transcriptional network in embryonic stem cells.

  2008influential reference
• Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

  2007cited by this paper
• Insulators: exploiting transcriptional and epigenetic mechanisms

  2006influential reference
• Hotspots of transcription factor colocalization in the genome of Drosophila melanogaster

  2006influential reference
• Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.

  2005cited by this paper
• DNA methylation and human disease

  2005cited by this paper
• Core transcriptional regulatory circuitry in human embryonic stem cells.

  2005influential reference
• TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes

  2005cited by this paper
• Discovery of functional noncoding elements by digital analysis of chromatin structure.

  2004cited by this paper
• The UCSC Genome Browser Database

  2003cited by this paper
• Largest Subunits of the Human SWI/SNF Chromatin-remodeling Complex Promote Transcriptional Activation by Steroid Hormone Receptors*

  2002cited by this paper
• The RFX Family Interacts at the Collagen (COL1A2) Start Site and Represses Transcription*

  2002cited by this paper
• Transcriptional Gene Regulation in Eukaryotes

  2001cited by this paper
• Transcriptional Regulation of the Antioxidant Response Element

  2000cited by this paper
• Identification and characterization of human ZNF274 cDNA, which encodes a novel kruppel-type zinc-finger protein having nucleolar targeting ability.

  2000cited by this paper
• Transcriptional Regulation of the Antioxidant Response Element ACTIVATION BY Nrf2 AND REPRESSION BY MafK*

  2000cited by this paper
• Locus control regions: coming of age at a decade plus.

  1999cited by this paper
• Assignment Problems

  1998cited by this paper
• AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression

  1997cited by this paper
• The shape of life, genes, development, and the evolution of animal form

  1996cited by this paper
• Chromatin structure and gene expression.

  1996cited by this paper
• Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony.

  1994cited by this paper
• Nuclease hypersensitive sites in chromatin.

  1988cited by this paper
• CONFIDENCE LIMITS ON PHYLOGENIES: AN APPROACH USING THE BOOTSTRAP

  1985influential reference
• A Method for Comparing Two Hierarchical Clusterings

  1983cited by this paper
• Stability of Two Hierarchical Grouping Techniques Case I: Sensitivity to Data Errors

  1974cited by this paper

• Genome-wide mapping of 5ʹ-aldehyde terminus induced by reactive oxygen species

  2025cites this paper
• Epigenetic basis for the establishment of ruminal tissue-specific functions in bovine fetuses and adults.

  2024cites this paper
• Long-range transcription factor binding sites clustered regions may mediate transcriptional regulation through phase-separation interactions in early human embryo

  2024cites this paper
• MMF-ATAC: A User-friendly Web Server for Multiple Motifs Finding on ATAC-seq Data

  2024cites this paper
• Stratifying TAD boundaries pinpoints focal genomic regions of regulation, damage, and repair

  2024cites this paper
• The developmental and evolutionary characteristics of transcription factor binding site clustered regions based on an explainable machine learning model

  2024influential citation
• MMGAT: a graph attention network framework for ATAC-seq motifs finding

  2024cites this paper
• Nucleotide alterations in the HLA-C class I gene can cause aberrant splicing and marked changes in RNA levels in a polymorphic context-dependent manner

  2024cites this paper
• CLIC3 interacts with NAT10 to inhibit N4-acetylcytidine modification of p21 mRNA and promote bladder cancer progression

  2024cites this paper
• Identification of transcription factor high accumulation DNA zones

  2023cites this paper
• Detection of features predictive of microRNA targets by integration of network data

  2022cites this paper
• Regulatory patterns analysis of transcription factor binding site clustered regions and identification of key genes in endometrial cancer

  2022influential citation
• Saccharomyces cerevisiae cis-acting DNA sequences curation pipeline (Sc-cADSs-CP): Master transcription factors prediction in yeasts

  2022cites this paper
• HIV- 1 lentivirus tethering to the genome is associated with transcription factor binding sites found in genes that favour virus survival

  2022cites this paper
• Mechanisms of enhancer action: the known and the unknown

  2021cites this paper
• Integrated transcription factor profiling with transcriptome analysis identifies L1PA2 transposons as global regulatory modulators in a breast cancer model

  2021cites this paper
• Epigenomic signatures on paralogous genes reveal underappreciated universality of active histone codes adopted across animals

  2021cites this paper
• Assessing deep learning methods in cis-regulatory motif finding based on genomic sequencing data

  2021cites this paper
• The Regulation of Target Genes by Co-occupancy of Transcription Factors, c-Myc and Mxi1 with Max in the Mouse Cell Line

  2020cites this paper
• L1PA2 transposons contribute abundant regulatory sequences in MCF7 breast cancer cell line

  2020cites this paper
• Determination of genetic effects and functional SNPs of bovine HTR1B gene on milk fatty acid traits

  2020cites this paper
• Intronic regions of the human coagulation factor VIII gene harboring transcription factor binding sites with a strong bias towards the short-interspersed elements

  2020cites this paper
• Isolation and characterization of putative liver-specific enhancers in proboscis monkey (Nasalis larvatus)

  2019cites this paper
• In-silico evidences of regulatory roles of WT1 transcription factor binding sites on the intervening sequences of the human Bcl-2 gene

  2018influential citation
• Advances of DNase-seq for mapping active gene regulatory elements across the genome in animals.

  2018cites this paper
• MYCN is amplified during S phase, and c-myb is involved in controlling MYCN expression and amplification in MYCN-amplified neuroblastoma cell lines

  2018cites this paper
• Borders of Cis-Regulatory DNA Sequences Preferentially Harbor the Divergent Transcription Factor Binding Motifs in the Human Genome

  2018cites this paper
• The borders of cis-regulatory DNA sequences harbor the divergent transcription factor binding motifs in the human genome

  2018cites this paper
• Exploring spatially adjacent TFBS-clustered regions with Hi-C data

  2017cites this paper
• Delineating the Transcriptional Mechanisms in Immunity behind Allergy and Asthma: Milestones and Challenges Ahead

  2017cites this paper
• Identification of introns harboring functional sequence elements through positional conservation

  2017cites this paper
• RPI-Bind: a structure-based method for accurate identification of RNA-protein binding sites

  2017cites this paper
• Efficient Wideband Numerical Simulations for Nanostructures Employing a Drude-Critical Points (DCP) Dispersive Model

  2017cites this paper
• Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription

  2016cites this paper
• INSECT 2.0: a web-server for genome-wide cis-regulatory modules prediction

  2016cites this paper
• iFORM: Incorporating Find Occurrence of Regulatory Motifs

  2016cites this paper
• Identification of HOT Regions in the Human Genome Using Differential Chromatin Modifications

  2016cites this paper
• FARNA: knowledgebase of inferred functions of non-coding RNA transcripts

  2016cites this paper
• Protein Interaction Networks in Health and Disease

  2016cites this paper
• Gene expression signatures of human cell and tissue longevity

  2016cites this paper
• Mechanisms of gene activation by metazoan enhancers : New insights and opportunities from high-throughput approaches

  2016cites this paper
• Next generation sequencing technology and genomewide data analysis: Perspectives for retinal research.

  2016cites this paper
• Functional annotation of HOT regions in the human genome: implications for human disease and cancer

  2015cites this paper
• Detecting modules in biological networks by edge weight clustering and entropy significance

  2015cites this paper
• Modeling co-occupancy of transcription factors using chromatin features

  2015cites this paper