Finding distal regulatory elements in the human genome.

Transcriptional regulation of human genes depends not only on promoters and nearby cis-regulatory elements, but also on distal regulatory elements such as enhancers, insulators, locus control regions, and silencing elements, which are often located far away from the genes they control. Our knowledge of human distal regulatory elements is very limited, but the last several years have seen rapid progress in the development of strategies to identify these long-range regulatory sequences throughout the human genome. Here, we review these advances, focusing on two important classes of distal regulatory sequences-enhancers and insulators.

[1]  Dustin E. Schones,et al.  Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. , 2008, Genome research.

[2]  R. Tjian,et al.  Orchestrated response: a symphony of transcription factors for gene control. , 2000, Genes & development.

[3]  J. Peters,et al.  How cohesin and CTCF cooperate in regulating gene expression , 2009, Chromosome Research.

[4]  H. Aburatani,et al.  Cohesin mediates transcriptional insulation by CCCTC-binding factor , 2008, Nature.

[5]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[6]  Michael R. Green,et al.  Transcriptional regulatory elements in the human genome. , 2006, Annual review of genomics and human genetics.

[7]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[8]  K. Sandhu,et al.  Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions , 2006, Nature Genetics.

[9]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[10]  J. Dekker A closer look at long-range chromosomal interactions. , 2003, Trends in biochemical sciences.

[11]  A. Philippakis,et al.  Compact, universal DNA microarrays to comprehensively determine transcription-factor binding site specificities , 2006, Nature Biotechnology.

[12]  Jane M J Lin,et al.  Identification and Characterization of Cell Type–Specific and Ubiquitous Chromatin Regulatory Structures in the Human Genome , 2007, PLoS genetics.

[13]  K. Nasmyth,et al.  Ordered Recruitment of Transcription and Chromatin Remodeling Factors to a Cell Cycle– and Developmentally Regulated Promoter , 2016, Cell.

[14]  C. Glass,et al.  The coregulator exchange in transcriptional functions of nuclear receptors. , 2000, Genes & development.

[15]  Daniel E. Newburger,et al.  Variation in Homeodomain DNA Binding Revealed by High-Resolution Analysis of Sequence Preferences , 2008, Cell.

[16]  Alexander E. Kel,et al.  TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes , 2005, Nucleic Acids Res..

[17]  R. Young,et al.  Rapid analysis of the DNA-binding specificities of transcription factors with DNA microarrays , 2004, Nature Genetics.

[18]  D. Reinberg,et al.  Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. , 2001, Genes & development.

[19]  Michael Q. Zhang,et al.  Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome , 2007, Cell.

[20]  Chunhui Hou,et al.  CTCF-dependent enhancer-blocking by alternative chromatin loop formation , 2008, Proceedings of the National Academy of Sciences.

[21]  Job Dekker,et al.  Long-range chromosomal interactions and gene regulation. , 2008, Molecular bioSystems.

[22]  A. West,et al.  Insulators: many functions, many mechanisms. , 2002, Genes & development.

[23]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[24]  Tom Maniatis,et al.  Transcriptional activation: A complex puzzle with few easy pieces , 1994, Cell.

[25]  G. Felsenfeld,et al.  We gather together: insulators and genome organization. , 2007, Current opinion in genetics & development.

[26]  Martha L. Bulyk,et al.  UniPROBE: an online database of protein binding microarray data on protein–DNA interactions , 2008, Nucleic Acids Res..

[27]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[28]  P. Fraser,et al.  Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus , 2009, Nature.

[29]  G. Stormo,et al.  Analysis of Homeodomain Specificities Allows the Family-wide Prediction of Preferred Recognition Sites , 2008, Cell.

[30]  I. Talianidis,et al.  Dynamics of enhancer-promoter communication during differentiation-induced gene activation. , 2002, Molecular cell.

[31]  Nathaniel D. Heintzman,et al.  The gateway to transcription: identifying, characterizing and understanding promoters in the eukaryotic genome , 2007, Cellular and Molecular Life Sciences.

[32]  S. Lomvardas,et al.  Modifying Gene Expression Programs by Altering Core Promoter Chromatin Architecture , 2002, Cell.

[33]  M. Groudine,et al.  Controlling the double helix , 2003, Nature.

[34]  I. Talianidis,et al.  Coordination of PIC Assembly and Chromatin Remodeling During Differentiation-Induced Gene Activation , 2002, Science.

[35]  R. Kingston,et al.  ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. , 1999, Genes & development.

[36]  Cameron S. Osborne,et al.  Active genes dynamically colocalize to shared sites of ongoing transcription , 2004, Nature Genetics.

[37]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[38]  Nathaniel D. Heintzman,et al.  Histone modifications at human enhancers reflect global cell-type-specific gene expression , 2009, Nature.

[39]  Nathaniel D. Heintzman,et al.  Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome , 2007, Nature Genetics.

[40]  Juan M. Vaquerizas,et al.  A census of human transcription factors: function, expression and evolution , 2009, Nature Reviews Genetics.

[41]  R. Kornberg,et al.  Mediator of transcriptional regulation. , 2000, Annual review of biochemistry.

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

[43]  T. Mikkelsen,et al.  Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites , 2007, Proceedings of the National Academy of Sciences.

[44]  Pierre Chartrand,et al.  Genome-wide scanning of HoxB1-associated loci in mouse ES cells using an open-ended Chromosome Conformation Capture methodology , 2006, Chromosome Research.

[45]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[46]  A. West,et al.  Insulators and boundaries: versatile regulatory elements in the eukaryotic genome. , 2001, Science.

[47]  Xiang-Dong Fu,et al.  Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules , 2008, Proceedings of the National Academy of Sciences.

[48]  R. Ghirlando,et al.  Chromatin boundaries and chromatin domains. , 2004, Cold Spring Harbor symposia on quantitative biology.

[49]  Daniel E. Newburger,et al.  Diversity and Complexity in DNA Recognition by Transcription Factors , 2009, Science.

[50]  C. Glass,et al.  Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. , 2006, Genes & development.

[51]  B. Steensel,et al.  Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C) , 2006, Nature Genetics.

[52]  C. Nusbaum,et al.  Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. , 2006, Genome research.

[53]  A. Visel,et al.  ChIP-seq accurately predicts tissue-specific activity of enhancers , 2009, Nature.

[54]  G. Church,et al.  Exploring the DNA-binding specificities of zinc fingers with DNA microarrays , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[55]  K. Nasmyth,et al.  Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter. , 1999, Cell.

[56]  M. Ptashne,et al.  Transcriptional activation by recruitment , 1997, Nature.

[57]  R. Young,et al.  Transcription of eukaryotic protein-coding genes. , 2000, Annual review of genetics.

[58]  Wyeth W. Wasserman,et al.  JASPAR: an open-access database for eukaryotic transcription factor binding profiles , 2004, Nucleic Acids Res..

[59]  Hui Ling Chen,et al.  CTCF Mediates Interchromosomal Colocalization Between Igf2/H19 and Wsb1/Nf1 , 2006, Science.

[60]  A. West,et al.  The Protein CTCF Is Required for the Enhancer Blocking Activity of Vertebrate Insulators , 1999, Cell.

[61]  Rolf Ohlsson,et al.  CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[62]  J. T. Kadonaga,et al.  The RNA polymerase II core promoter: a key component in the regulation of gene expression. , 2002, Genes & development.