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Linking Enhancer to Epigenetics: New Way to Think About Human Diseases

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Handbook of Nutrition, Diet, and Epigenetics

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Abstract

The spatiotemporal-specific gene expression in different cell types from a common genome of a multicellular organism is the basis of cellular function, tissue development, and homeostasis of the multicellular life. Dysregulation of the spatiotemporal gene expression pattern often leads to disease pathogenesis. Enhancers define distinct cell identities by determining the precise spatiotemporal patterns of gene expression during development. Enhancers can also respond to diverse environmental signals including different nutritional status to fine-tune the cellular functional demands. Thus, unraveling the intricate regulatory process of enhancer in governing gene expression has become a major thrust of the biological field to decipher developmental process and disease pathogenesis.

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Abbreviations

3C:

Chromosome conformation capture

AF9:

ALL1-fused gene from chromosome 9

AFF:

AF4/FMR2

AML:

Acute myeloid leukemia

BET:

Bromodomain and extra-terminal

BRD4:

Bromodomain-containing protein 4

Cas9:

CRISPR-associated protein-9 nuclease

CBP:

CREB-binding protein

CBS:

CTCF-binding site

CDK9:

Cyclin-dependent kinase 9

CdLS:

Cornelia de Lange syndrome

CML:

Chronic myelogenous leukemia

COMPASS:

Complex proteins associated with set1

CREB:

Cyclic AMP-responsive element-binding protein

CRISPR:

Clustered regularly interspaced short palindromic repeat

CTCF:

CCCTC-binding factor

CTD:

C-terminal domain

DHS:

DNase I hypersensitive site

DIPG:

Diffuse intrinsic pontine glioma

DRB:

5,6-Dichloro-1-ß-D-ribofuranosylbenzimidazole

DSIF:

DRB-sensitivity-inducing factor

E2:

17β-estradiol

EGF:

Epidermal growth factor

ELL:

Eleven-nineteen Lys-rich leukemia

ENCODE:

Encyclopedia of DNA Elements

ENL:

Eleven-nineteen leukemia

eRNA:

Enhancer RNA

ERα:

Estrogen receptor-α

EZH2:

Enhancer of zeste homolog 2

Fox:

Forkhead box

GTF:

General transcription factor

GWAS:

Genome-wide association study

H3K27ac:

Histone H3 lysine 27 acetylation

H3K27me3:

Histone H3 lysine 27 trimethylation

H3K4me1:

Histone H3 lysine 4 monomethylation

H3K4me3:

Histone H3 lysine 4 trimethylation

HEXIM1:

Hexamethylene bisacetamide inducible 1

HEXIM2:

Hexamethylene bisacetamide inducible 2

HGP:

Human Genome Project

HL:

Hodgkin lymphoma

ICGC:

International Cancer Genome Consortium

IEG:

Immediate early gene

JmjC:

Jumonji C

LNA:

Locked nucleic acid antisense oligonucleotide

LSD1:

Lysine (K)-specific demethylase 1A

MLL:

Mixed lineage leukemia

modENCODE:

Model Organism Encyclopedia of DNA Elements

mRNA:

Messenger RNA

NELF:

Negative elongation factor

NFR:

Nucleosome-free region

NGS:

Next-generation sequencing

NHL:

Non-Hodgkin lymphoma

nt:

Nucleotide

NuRD:

Nucleosome remodeling and histone deacetylation

PcG:

Polycomb group

PIC:

Pre-initiation complex

PPARγ:

Peroxisome proliferator-activated receptor gamma

PRC2:

Polycomb repressive complex 2

P-TEFb:

Positive transcription elongation factor b

RNA Pol II:

RNA polymerase II

RRM:

RNA recognition motif

rRNA:

Ribosomal RNA

SEC:

Super elongation complex

SEC-L2:

SEC-like 2

SEC-L3:

SEC-like 3

siRNA:

Small interfering RNA

SNP:

Single nucleotide polymorphism

snRNP:

Small nuclear ribonucleoprotein particle

SV40:

Simian virus 40

TAD:

Topologically associating domain

T-ALL:

T-cell acute lymphoblastic leukemia

TCGA:

The Cancer Genome Atlas

TPR:

Tetratricopeptide-repeats

Trr:

Trithorax related

TrxG:

Trithorax group

TSS:

Transcription start site

TZD:

Thiazolidinedione

UTX:

Ubiquitously transcribed X chromosome tetratricopeptide repeat protein

References

  • Adelman K, Lis JT (2012) Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet 13(10):720–731

    Article  CAS  Google Scholar 

  • Arner E, Daub CO et al (2015) Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347(6225):1010–1014

    Article  CAS  Google Scholar 

  • Banerji J, Rusconi S et al (1981) Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 27(2 Pt 1):299–308

    Article  CAS  Google Scholar 

  • Banerji J, Olson L et al (1983) A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell 33(3):729–740

    Article  CAS  Google Scholar 

  • Buenrostro JD, Giresi PG et al (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10(12):1213–1218

    Article  CAS  Google Scholar 

  • Calo E, Wysocka J (2013) Modification of enhancer chromatin: what, how, and why? Mol Cell 49(5):825–837

    Article  CAS  Google Scholar 

  • Chen K, Chen Z et al (2015) Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes. Nat Genet 47(10):1149–1157

    Article  CAS  Google Scholar 

  • Creyghton MP, Cheng AW et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 107(50):21931–21936

    Article  CAS  Google Scholar 

  • de Wit E, Vos ES et al (2015) CTCF binding polarity determines chromatin looping. Mol Cell 60(4):676–684

    Article  Google Scholar 

  • Di Croce L, Helin K (2013) Transcriptional regulation by Polycomb group proteins. Nat Struct Mol Biol 20(10):1147–1155

    Article  Google Scholar 

  • Dixon JR, Selvaraj S et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485(7398):376–380

    Article  CAS  Google Scholar 

  • Dorsett D (2011) Cohesin: genomic insights into controlling gene transcription and development. Curr Opin Genet Dev 21(2):199–206

    Article  CAS  Google Scholar 

  • Filippakopoulos P, Knapp S (2014) Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 13(5):337–356

    Article  CAS  Google Scholar 

  • Gardini A, Baillat D et al (2014) Integrator regulates transcriptional initiation and pause release following activation. Mol Cell 56(1):128–139

    Article  CAS  Google Scholar 

  • Gui Y, Guo G et al (2011) Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet 43(9):875–878

    Article  CAS  Google Scholar 

  • Guo Y, Xu Q et al (2015) CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell 162(4):900–910

    Article  CAS  Google Scholar 

  • Haakonsson AK, Stahl Madsen M et al (2013) Acute genome-wide effects of rosiglitazone on PPARgamma transcriptional networks in adipocytes. Mol Endocrinol 27(9):1536–1549

    Article  CAS  Google Scholar 

  • Hannenhalli S, Kaestner KH (2009) The evolution of fox genes and their role in development and disease. Nat Rev Genet 10(4):233–240

    Article  CAS  Google Scholar 

  • Heintzman ND, Stuart RK et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39(3):311–318

    Article  CAS  Google Scholar 

  • Herz HM, Mohan M et al (2012) Enhancer-associated H3K4 monomethylation by Trithorax-related, the drosophila homolog of mammalian Mll3/Mll4. Genes Dev 26(23):2604–2620

    Article  CAS  Google Scholar 

  • Hu D, Gao X et al (2013) The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol Cell Biol 33(23):4745–4754

    Article  CAS  Google Scholar 

  • Hudson TJ, Anderson W et al (2010) International network of cancer genome projects. Nature 464(7291):993–998

    Article  CAS  Google Scholar 

  • Izumi K, Nakato R et al (2015) Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet 47(4):338–344

    Article  CAS  Google Scholar 

  • Jin Q, Yu LR et al (2011) Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J 30(2):249–262

    Article  CAS  Google Scholar 

  • Kagey MH, Newman JJ et al (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467(7314):430–435

    Article  CAS  Google Scholar 

  • Kaikkonen MU, Spann NJ et al (2013) Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51(3):310–325

    Article  CAS  Google Scholar 

  • Kim TK, Hemberg M et al (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465(7295):182–187

    Article  CAS  Google Scholar 

  • Lai F, Gardini A et al (2015) Integrator mediates the biogenesis of enhancer RNAs. Nature 525(7569):399–403

    Article  CAS  Google Scholar 

  • Lee JE, Wang C et al (2013) H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. elife 2:e01503

    Article  Google Scholar 

  • Levine M (2011) Paused RNA polymerase II as a developmental checkpoint. Cell 145(4):502–511

    Article  CAS  Google Scholar 

  • Lewis PW, Muller MM et al (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340(6134):857–861

    Article  CAS  Google Scholar 

  • Li G, Ruan X et al (2012) Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148(1–2):84–98

    Article  CAS  Google Scholar 

  • Li W, Notani D et al (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498(7455):516–520

    Article  CAS  Google Scholar 

  • Lieberman-Aiden E, van Berkum NL et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289–293

    Article  CAS  Google Scholar 

  • Lin C, Smith ER et al (2010) AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell 37(3):429–437

    Article  CAS  Google Scholar 

  • Lin C, Garrett AS et al (2011) Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC). Genes Dev 25(14):1486–1498

    Article  CAS  Google Scholar 

  • Lin C, Garruss AS et al (2013) The RNA pol II elongation factor Ell3 marks enhancers in ES cells and primes future gene activation. Cell 152(1–2):144–156

    Article  CAS  Google Scholar 

  • Luo Z, Lin C (2016) Enhancer, epigenetics, and human disease. Curr Opin Genet Dev 36:27–33

    Article  CAS  Google Scholar 

  • Luo Z, Lin C et al (2012a) The super elongation complex family of RNA polymerase II elongation factors: gene target specificity and transcriptional output. Mol Cell Biol 32(13):2608–2617

    Article  CAS  Google Scholar 

  • Luo Z, Lin C et al (2012b) The super elongation complex (SEC) family in transcriptional control. Nat Rev Mol Cell Biol 13(9):543–547

    Article  CAS  Google Scholar 

  • Mannini L, Lamaze FC et al (2015) Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome. Sci Rep 5:16803

    Article  CAS  Google Scholar 

  • Maurano MT, Humbert R et al (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337(6099):1190–1195

    Article  CAS  Google Scholar 

  • Mendenhall EM, Williamson KE et al (2013) Locus-specific editing of histone modifications at endogenous enhancers. Nat Biotechnol 31(12):1133–1136

    Article  CAS  Google Scholar 

  • Morin RD, Johnson NA et al (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 42(2):181–185

    Article  CAS  Google Scholar 

  • Morin RD, Mendez-Lago M et al (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476(7360):298–303

    Article  CAS  Google Scholar 

  • Ntziachristos P, Tsirigos A et al (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514(7523):513–517

    Article  CAS  Google Scholar 

  • Pasquali L, Gaulton KJ et al (2014) Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet 46(2):136–143

    Article  CAS  Google Scholar 

  • Pekowska A, Benoukraf T et al (2011) H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J 30(20):4198–4210

    Article  CAS  Google Scholar 

  • Piunti A, Shilatifard A (2016) Epigenetic balance of gene expression by Polycomb and COMPASS families. Science 352(6290):aad9780

    Article  Google Scholar 

  • Qi W, Chan H et al (2012) Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci USA 109(52):21360–21365

    Article  CAS  Google Scholar 

  • Rada-Iglesias A, Bajpai R et al (2011) A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470(7333):279–283

    Article  CAS  Google Scholar 

  • Schaukowitch K, Joo JY et al (2014) Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell 56(1):29–42

    Article  CAS  Google Scholar 

  • Sneeringer CJ, Scott MP et al (2010) Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B- cell lymphomas. Proc Natl Acad Sci USA 107(49):20980–20985

    Article  CAS  Google Scholar 

  • Soccio RE, Chen ER et al (2015) Genetic variation determines PPARgamma function and anti-diabetic drug response in vivo. Cell 162(1):33–44

    Article  CAS  Google Scholar 

  • Takahashi H, Parmely TJ et al (2011) Human mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 146(1):92–104

    Article  CAS  Google Scholar 

  • Thurman RE, Rynes E et al (2012) The accessible chromatin landscape of the human genome. Nature 489(7414):75–82

    Article  CAS  Google Scholar 

  • Tie F, Banerjee R et al (2012) Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27. Mol Cell Biol 32(12):2323–2334

    Article  CAS  Google Scholar 

  • Tuan D, Kong S et al (1992) Transcription of the hypersensitive site HS2 enhancer in erythroid cells. Proc Natl Acad Sci USA 89(23):11219–11223

    Article  CAS  Google Scholar 

  • Van der Meulen J, Sanghvi V et al (2015) The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood 125(1):13–21

    Article  Google Scholar 

  • van Haaften G, Dalgliesh GL et al (2009) Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 41(5):521–523

    Article  Google Scholar 

  • Varambally S, Dhanasekaran SM et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419(6907):624–629

    Article  CAS  Google Scholar 

  • Weinstein JN, Collisson EA et al (2013) The cancer genome atlas pan-cancer analysis project. Nat Genet 45(10):1113–1120

    Article  Google Scholar 

  • Whyte WA, Bilodeau S et al (2012) Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482(7384):221–225

    Article  CAS  Google Scholar 

  • Wu G, Broniscer A et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44(3):251–253

    Article  CAS  Google Scholar 

  • Yamaguchi H, Hung MC (2014) Regulation and role of EZH2 in cancer. Cancer Res Treat J Korean Cancer Assoc 46(3):209–222

    Article  CAS  Google Scholar 

  • Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25(21):2227–2241

    Article  CAS  Google Scholar 

  • Zuin J, Dixon JR et al (2014) Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci USA 111(3):996–1001

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Life Sciences, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu, China

    Zhuojuan Luo & Chengqi Lin

Authors
  1. Zhuojuan Luo
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  2. Chengqi Lin
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Correspondence to Chengqi Lin .

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Editors and Affiliations

  1. School of Life Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Sciences and Medicine, King’s College London, London, UK

    Victor R. Preedy

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Luo, Z., Lin, C. (2019). Linking Enhancer to Epigenetics: New Way to Think About Human Diseases. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-55530-0_66

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  • DOI: https://doi.org/10.1007/978-3-319-55530-0_66

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