Transcriptional Enhancers: Bridging the Genome and Phenome.

Enhancers play a major role in animal development by modulating spatiotemporal expression of genes. They interact with sequence-specific transcriptional regulators in response to internal and external cues to bring about transcriptional changes, thus serving as the critical link between an organism's genome and its phenotypic traits. Deciphering the biology of enhancers is a key to understanding the genetic basis of common human diseases. Although a large number of candidate enhancers have been annotated through genome-wide analyses of chromatin accessibility, transcription factor binding, and histone modification in diverse cell types, efforts to characterize their biological roles in human diseases have only begun. Recent experiments have suggested a role for the three-dimensional chromatin architecture in regulation of gene expression by enhancers.

[1]  O. Delaneau,et al.  Population Variation and Genetic Control of Modular Chromatin Architecture in Humans , 2015, Cell.

[2]  Judith B. Zaugg,et al.  Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions , 2015, Cell.

[3]  R. Sandberg,et al.  Genome-wide mapping of promoter-anchored interactions with close to single-enhancer resolution , 2015, Genome Biology.

[4]  Eric S. Lander,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2015, Cell.

[5]  Nir Friedman,et al.  Mapping Nucleosome Resolution Chromosome Folding in Yeast by Micro-C , 2015, Cell.

[6]  Howard Y. Chang,et al.  Single-cell chromatin accessibility reveals principles of regulatory variation , 2015, Nature.

[7]  Andrew C. Adey,et al.  Multiplex single-cell profiling of chromatin accessibility by combinatorial cellular indexing , 2015, Science.

[8]  A. Visel,et al.  Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions , 2015, Cell.

[9]  Matthew D. Schultz,et al.  Human Body Epigenome Maps Reveal Noncanonical DNA Methylation Variation , 2015, Nature.

[10]  Neville E. Sanjana,et al.  High-throughput functional genomics using CRISPR–Cas9 , 2015, Nature Reviews Genetics.

[11]  L. Kruglyak,et al.  The role of regulatory variation in complex traits and disease , 2015, Nature Reviews Genetics.

[12]  Charles Y. Lin,et al.  Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. , 2015, Molecular cell.

[13]  Pedro P. Rocha,et al.  CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation , 2015, Science.

[14]  D. Odom,et al.  Comparative Hi-C Reveals that CTCF Underlies Evolution of Chromosomal Domain Architecture , 2015, Cell reports.

[15]  F. Collins,et al.  A new initiative on precision medicine. , 2015, The New England journal of medicine.

[16]  Jing Liang,et al.  Chromatin architecture reorganization during stem cell differentiation , 2015, Nature.

[17]  Michael Q. Zhang,et al.  Integrative analysis of haplotype-resolved epigenomes across human tissues , 2015, Nature.

[18]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[19]  Jonathan K. Pritchard,et al.  The Genetic and Mechanistic Basis for Variation in Gene Regulation , 2015, PLoS genetics.

[20]  William Stafford Noble,et al.  Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes , 2014, Nature Methods.

[21]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[22]  Jennifer A. Mitchell,et al.  A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential , 2014, Genes & development.

[23]  Bing Ren,et al.  CRISPR Reveals a Distal Super-Enhancer Required for Sox2 Expression in Mouse Embryonic Stem Cells , 2014, PloS one.

[24]  J. Doudna,et al.  The new frontier of genome engineering with CRISPR-Cas9 , 2014, Science.

[25]  Fidencio J. Neri,et al.  Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution , 2014, Science.

[26]  Shane J. Neph,et al.  A comparative encyclopedia of DNA elements in the mouse genome , 2014, Nature.

[27]  Lee E. Edsall,et al.  5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. , 2014, Molecular cell.

[28]  Nick Kepper,et al.  Targeted Chromatin Capture (T2C): a novel high resolution high throughput method to detect genomic interactions and regulatory elements , 2014, Epigenetics & Chromatin.

[29]  B. Ren,et al.  The 3D genome in transcriptional regulation and pluripotency. , 2014, Cell stem cell.

[30]  Robert Tjian,et al.  Looping Back to Leap Forward: Transcription Enters a New Era , 2014, Cell.

[31]  T. Meehan,et al.  An atlas of active enhancers across human cell types and tissues , 2014, Nature.

[32]  Edwin Smith,et al.  Enhancer biology and enhanceropathies , 2014, Nature Structural &Molecular Biology.

[33]  M. Gobbi,et al.  Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment , 2014, Nature Genetics.

[34]  R. Sandberg,et al.  Single-Cell RNA-Seq Reveals Dynamic, Random Monoallelic Gene Expression in Mammalian Cells , 2014, Science.

[35]  A. Visel,et al.  Rapid and Pervasive Changes in Genome-wide Enhancer Usage during Mammalian Development , 2013, Cell.

[36]  Jesse R. Dixon,et al.  Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells , 2013, Proceedings of the National Academy of Sciences.

[37]  F. Tang,et al.  Single-cell methylome landscapes of mouse embryonic stem cells and early embryos analyzed using reduced representation bisulfite sequencing , 2013, Genome research.

[38]  Howard Y. Chang,et al.  Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position , 2013, Nature Methods.

[39]  Job Dekker,et al.  Organization of the Mitotic Chromosome , 2013, Science.

[40]  R. Young,et al.  Super-Enhancers in the Control of Cell Identity and Disease , 2013, Cell.

[41]  Bing Ren,et al.  Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers , 2013, Science.

[42]  G. Hon,et al.  Adult tissue methylomes harbor epigenetic memory at embryonic enhancers , 2013, Nature Genetics.

[43]  A. Tanay,et al.  Single cell Hi-C reveals cell-to-cell variability in chromosome structure , 2013, Nature.

[44]  J. Shendure,et al.  Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model , 2013, Nature Genetics.

[45]  A. Gnirke,et al.  Charting a dynamic DNA methylation landscape of the human genome , 2013, Nature.

[46]  B. Cohen,et al.  Massively parallel in vivo enhancer assay reveals that highly local features determine the cis-regulatory function of ChIP-seq peaks , 2013, Proceedings of the National Academy of Sciences.

[47]  T. Mikkelsen,et al.  Systematic dissection of regulatory motifs in 2000 predicted human enhancers using a massively parallel reporter assay. , 2013, Genome research.

[48]  Yi Zhang,et al.  Genome-wide Analysis Reveals TET- and TDG-Dependent 5-Methylcytosine Oxidation Dynamics , 2013, Cell.

[49]  P. Jin,et al.  Genome-wide Profiling of 5-Formylcytosine Reveals Its Roles in Epigenetic Priming , 2013, Cell.

[50]  David A. Orlando,et al.  Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes , 2013, Cell.

[51]  J. Wysocka,et al.  Modification of enhancer chromatin: what, how, and why? , 2013, Molecular cell.

[52]  Łukasz M. Boryń,et al.  Genome-Wide Quantitative Enhancer Activity Maps Identified by STARR-seq , 2013, Science.

[53]  Wei Xie,et al.  RFECS: A Random-Forest Based Algorithm for Enhancer Identification from Chromatin State , 2013, PLoS Comput. Biol..

[54]  William Stafford Noble,et al.  Unsupervised pattern discovery in human chromatin structure through genomic segmentation , 2012, Nature Methods.

[55]  Shane J. Neph,et al.  Circuitry and Dynamics of Human Transcription Factor Regulatory Networks , 2012, Cell.

[56]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[57]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[58]  Nathan C. Sheffield,et al.  The accessible chromatin landscape of the human genome , 2012, Nature.

[59]  Simon C. Potter,et al.  Mapping cis- and trans-regulatory effects across multiple tissues in twins , 2012, Nature Genetics.

[60]  Lee E. Edsall,et al.  A map of the cis-regulatory sequences in the mouse genome , 2012, Nature.

[61]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[62]  G. Hon,et al.  Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome , 2012, Cell.

[63]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[64]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[65]  Joseph B Hiatt,et al.  Massively parallel functional dissection of mammalian enhancers in vivo , 2012, Nature Biotechnology.

[66]  A. Tanay,et al.  Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome , 2012, Cell.

[67]  Manolis Kellis,et al.  ChromHMM: automating chromatin-state discovery and characterization , 2012, Nature Methods.

[68]  Reza Kalhor,et al.  Genome architectures revealed by tethered chromosome conformation capture and population-based modeling , 2011, Nature Biotechnology.

[69]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[70]  Timothy J. Durham,et al.  "Systematic" , 1966, Comput. J..

[71]  Timothy J. Durham,et al.  Systematic analysis of chromatin state dynamics in nine human cell types , 2011, Nature.

[72]  Ryan A. Flynn,et al.  A unique chromatin signature uncovers early developmental enhancers in humans , 2011, Nature.

[73]  E. Lander.  Initial impact of the sequencing of the human genome , 2011, Nature.

[74]  Alkes L. Price,et al.  Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals , 2011, PLoS genetics.

[75]  Mark Groudine,et al.  Functional and Mechanistic Diversity of Distal Transcription Enhancers , 2011, Cell.

[76]  R. Young,et al.  Histone H3K27ac separates active from poised enhancers and predicts developmental state , 2010, Proceedings of the National Academy of Sciences.

[77]  M. Levine.  Transcriptional Enhancers in Animal Development and Evolution , 2010, Current Biology.

[78]  G. Hon,et al.  Next-generation genomics: an integrative approach , 2010, Nature Reviews Genetics.

[79]  Catalin C. Barbacioru,et al.  Tracing the Derivation of Embryonic Stem Cells from the Inner Cell Mass by Single-Cell RNA-Seq Analysis , 2010, Cell stem cell.

[80]  William Stafford Noble,et al.  A Three-Dimensional Model of the Yeast Genome , 2010, Nature.

[81]  F. Grosveld,et al.  High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology , 2009, Nature Methods.

[82]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

[83]  K. Frazer,et al.  Human genetic variation and its contribution to complex traits , 2009, Nature Reviews Genetics.

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

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

[86]  M. Daly,et al.  Genetic Mapping in Human Disease , 2008, Science.

[87]  Bing Ren,et al.  ChromaSig: A Probabilistic Approach to Finding Common Chromatin Signatures in the Human Genome , 2008, PLoS Comput. Biol..

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

[89]  Z. Weng,et al.  High-Resolution Mapping and Characterization of Open Chromatin across the Genome , 2008, Cell.

[90]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

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

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

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

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

[95]  Inna Dubchak,et al.  VISTA Enhancer Browser—a database of tissue-specific human enhancers , 2006, Nucleic Acids Res..

[96]  Alan M. Moses,et al.  In vivo enhancer analysis of human conserved non-coding sequences , 2006, Nature.

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

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

[99]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[100]  Leah Barrera,et al.  A high-resolution map of active promoters in the human genome , 2005, Nature.

[101]  C. Carlson,et al.  Mapping complex disease loci in whole-genome association studies , 2004, Nature.

[102]  D. Botstein,et al.  Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease , 2003, Nature Genetics.

[103]  G. Abecasis,et al.  Using haplotype blocks to map human complex trait loci. , 2003, Trends in genetics : TIG.

[104]  Clifford S. Deutschman,et al.  Transcription , 2003, The Quran: Word List (Volume 3).

[105]  M. Groudine,et al.  Regulation of β-globin gene expression: straightening out the locus , 1996 .

[106]  F. Grosveld,et al.  The regulation of human globin gene switching. , 1993, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[107]  F. Grosveld,et al.  Regulation of human globin gene switching. , 1993, Cold Spring Harbor symposia on quantitative biology.

[108]  F. Grosveld,et al.  Importance of globin gene order for correct developmental expression. , 1991, Genes & development.

[109]  D. Tuan,et al.  Mapping of DNase I-hypersensitive sites in the upstream DNA of human embryonic epsilon-globin gene in K562 leukemia cells. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[110]  D. Kioussis,et al.  β-Globin gene inactivation by DNA translocation in γβ-thalassaemi , 1983, Nature.

[111]  J. Banerji,et al.  Expression of a β-globin gene is enhanced by remote SV40 DNA sequences , 1981, Cell.

[112]  P. Chambon,et al.  The SV40 72 base repair repeat has a striking effect on gene expression both in SV40 and other chimeric recombinants. , 1981, Nucleic acids research.

[113]  M. Yaniv,et al.  Fine structure of the origin-proximal DNAase I-hypersensitive region in wild-type and EC mutant polyoma , 1981, Cell.

[114]  M. Groudine,et al.  Chromosomal subunits in active genes have an altered conformation. , 1976, Science.

[115]  D. Tuan,et al.  Mapping of DNase I-hypersensitive sites in the upstream DNA of human embryonic E-globin gene in K 562 leukemia cells ( gene expression / enhancer cores / HL 60 cells / c-myc gene / Southern blots ) , 2022 .