超级增强子调控基因表达的生物学作用及其在哺乳动物中的应用前景

doi:10.11843/j.issn.0366-6964.2021.012.002

摘要/Abstract

摘要： 超级增强子是一类包含多个普通增强子的大簇，主要富集高密度的转录因子、辅助因子及增强子相关表观修饰位点。与普通增强子相比，超级增强子具有更高的转录激活能力，在细胞类型特异性发育、分化以及肿瘤的发展进程中发挥关键作用。研究超级增强子在基因转录过程中的作用机制，对于揭示哺乳动物表型性状的分子机理具有十分重要的生物学意义。本文概述了超级增强子的概念、特性及鉴定方法，总结了超级增强子发挥作用的主要机制，最后对超级增强子调控动物重要表型的研究进展进行综述，并且结合超级增强子在哺乳动物方面的最新研究进展，讨论了其在哺乳类动物中的应用前景，旨在为超级增强子在动物重要性状表型研究中提供参考。

关键词: 超级增强子, 转录调控, 启动子, 增强子, 相变, 非编码RNA

Abstract: Super enhancers are a class of large clusters containing multiple enhancers, mainly enriched with a high density of transcription factors, cofactors and enhancer-associated epigenetic modification sites. Compared with enhancers, super enhancers have higher transcriptional activation capacity and play a key role in cell type-specific development, differentiation, and tumor development processes. Studying the mechanism of super-enhancer action in gene transcription is of great biological importance to reveal the molecular mechanism of mammalian phenotypic traits. This article outlines the concept, properties and identification methods of super enhancers, summarizes the main mechanisms of super enhancers function, and finally reviews the research progress of super enhancers in regulating important phenotypes of animals, and discusses their application prospects in mammals combined with the latest research progress of super enhancers, aiming to provide a reference for studying functions of super enhancer in important phenotypic traits in animals.

Key words: super enhancers, transcriptional regulation, promoter, enhancer, phase transition, non-coding RNA

中图分类号:

S813

赵磊, 康晓龙. 超级增强子调控基因表达的生物学作用及其在哺乳动物中的应用前景[J]. 畜牧兽医学报, 2021, 52(12): 3335-3345.

ZHAO Lei, KANG Xiaolong. The Biological Role of Super Enhancers in Regulating Gene Expression and Their Application Prospects in Mammals[J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(12): 3335-3345.

参考文献 80

[1]	BANERJI J, RUSCONI S, SCHAFFNER W.Expression of a β-globin gene is enhanced by remote SV40 DNA sequences[J].Cell, 1981, 27(2 Pt 1):299-308.
[2]	BANERJI J, OLSON L, SCHAFFNER W.A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes[J].Cell, 1983, 33(3):729-740.
[3]	PLANK J L, DEAN A.Enhancer function:mechanistic and genome-wide insights come together[J]. Mol Cell, 2014, 55(1):5-14.
[4]	CRAWFORD G E, HOLT I E, WHITTLE J, et al.Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS)[J].Genome Res, 2005, 16(1):123-131.
[5]	SHEFFIELD N C, THURMAN R E, SONG L Y, et al.Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions[J].Genome Res, 2013, 23(5):777-788.
[6]	ARNOLD P R, WELLS A D, LI X C.Diversity and emerging roles of enhancer RNA in regulation of gene expression and cell fate[J].Front Cell Dev Biol, 2020, 7:377.
[7]	吴志强, 米泽云.超级增强子在肿瘤研究中的进展[J].遗传, 2019, 41(1):41-51.WU Z Q, MI Z Y.Research progress of super enhancer in cancer[J].Hereditas (Beijing), 2019, 41(1):41-51.(in Chinese)
[8]	WHYTE W A, ORLANDO D A, HNISZ D, et al.Master transcription factors and mediator establish super-enhancers at key cell identity genes[J].Cell, 2013, 153(2):307-319.
[9]	WONG R W J, NGOC P C T, LEONG W Z, et al.Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia[J].Blood, 2017, 130(21):2326-2338.
[10]	HNISZ D, ABRAHAM B J, LEE T I, et al.Super-enhancers in the control of cell identity and disease[J].Cell, 2013, 155(4):934-947.
[11]	WITTE S, BRADLEY A, ENRIGHT A J, et al.High-density P300 enhancers control cell state transitions[J].BMC Genomics, 2015, 16:903.
[12]	HAH N, BENNER C, CHONG L W, et al.Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs[J].Proc Natl Acad Sci USA, 2015, 112(3):E297-E302.
[13]	ALVAREZ-DOMINGUEZ J R, KNOLL M, GROMATZKY A A, et al.The super-enhancer-derived alncRNA-EC7/bloodlinc potentiates red blood cell development in trans[J].Cell Rep, 2017, 19(12):2503-2514.
[14]	MANSOUR M R, ABRAHAM B J, ANDERS L, et al.An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element[J].Science, 2014, 346(6215):1373-1377.
[15]	HNISZ D, SCHUIJERS J, LIN C Y, et al.Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers[J].Mol Cell, 2015, 58(2):362-370.
[16]	HAY D, HUGHES J R, BABBS C, et al.Genetic dissection of the α-globin super-enhancer in vivo[J].Nat Genet, 2016, 48(8):895-903.
[17]	SHIN H Y, WILLI M, YOO K H, et al.Hierarchy within the mammary STAT5-driven Wap super-enhancer[J].Nat Genet, 2016, 48(8):904-911.
[18]	PARKER S C J, STITZEL M L, TAYLOR D L, et al.Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants[J].Proc Natl Acad Sci USA, 2013, 110(44):17921-17926.
[19]	KHAN A, MATHELIER A, ZHANG X G.Super-enhancers are transcriptionally more active and cell type-specific than stretch enhancers[J].Epigenetics, 2018, 13(9):910-922.
[20]	POTT S, LIEB J D.What are super-enhancers?[J].Nat Genet, 2015, 47(1):8-12.
[21]	VISEL A, BLOW M J, LI Z R, et al.ChIP-seq accurately predicts tissue-specific activity of enhancers[J].Nature, 2009, 457(7231):854-858.
[22]	DEKKER J, RIPPE K, DEKKER M, et al.Capturing chromosome conformation[J].Science, 2002, 295(5558):1306-1311.
[23]	SIMONIS M, KLOUS P, SPLINTER E, et al.Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C)[J].Nat Genet, 2006, 38(11):1348-1354.
[24]	DOSTIE J, RICHMOND T A, ARNAOUT R A, et al.Chromosome conformation capture carbon copy (5C):a massively parallel solution for mapping interactions between genomic elements[J].Genome Res, 2006, 16(10):1299-1309.
[25]	LIEBERMAN-AIDEN E, VAN BERKUM N L, WILLIAMS L, et al.Comprehensive mapping of long-range interactions reveals folding principles of the human genome[J].Science, 2009, 326(5950):289-293.
[26]	PENG Y L, ZHANG Y B.Enhancer and super-enhancer:positive regulators in gene transcription[J]. Animal Model Exp Med, 2018, 1(3):169-179.
[27]	CARTER D, CHAKALOVA L, OSBORNE C S, et al.Long-range chromatin regulatory interactions in vivo[J].Nat Genet, 2002, 32(4):623-626.
[28]	DENG W L, LEE J, WANG H X, et al.Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor[J].Cell, 2012, 149(6):1233-1244.
[29]	DIXON J R, SELVARAJ S, YUE F, et al.Topological domains in mammalian genomes identified by analysis of chromatin interactions[J].Nature, 2012, 485(7398):376-380.
[30]	ROWLEY M J, CORCES V G.Organizational principles of 3D genome architecture[J].Nat Rev Genet, 2018, 19(12):789-800.
[31]	FLYAMER I M, GASSLER J, IMAKAEV M, et al.Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition[J].Nature, 2017, 544(7648):110-114.
[32]	ROCHA P P, RAVIRAM R, BONNEAU R, et al.Breaking TADs:insights into hierarchical genome organization[J].Epigenomics, 2015, 7(4):523-526.
[33]	DOWEN J M, FAN Z P, HNISZ D, et al.Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes[J].Cell, 2014, 159(2):374-387.
[34]	KLOETGEN A, THANDAPANI P, NTZIACHRISTOS P, et al.Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia[J].Nat Genet, 2020, 52(4):388-400.
[35]	DENG R, HUANG J H, WANG Y, et al.Disruption of super-enhancer-driven tumor suppressor gene RCAN1.4 expression promotes the malignancy of breast carcinoma[J].Mol Cancer, 2020, 19(1):122.
[36]	CHEN J, XUE Y C.Emerging roles of non-coding RNAs in epigenetic regulation[J].Sci China Life Sci, 2016, 59(3):227-235.
[37]	CHEN J, CAI Z K, BAI M Z, et al.The RNA-binding protein ROD1/PTBP3 cotranscriptionally defines AID-loading sites to mediate antibody class switch in mammalian genomes[J].Cell Res, 2018, 28(10):981-995.
[38]	WANG Y T, NIE H, HE X Y, et al.The emerging role of super enhancer-derived noncoding RNAs in human cancer[J].Theranostics, 2020, 10(24):11049-11062.
[39]	OU C L, SUN Z Q, LI X Y, et al.MiR-590-5p, a density-sensitive microRNA, inhibits tumorigenesis by targeting YAP1 in colorectal cancer[J].Cancer Lett, 2017, 399:53-63.
[40]	ZHENG X, WANG J, WEI L Y, et al.Epstein-barr virus MicroRNA miR-BART5-3p inhibits p53 expression[J].J Virol, 2018, 92(23):e01022-18.
[41]	SUZUKI H I, YOUNG R A, SHARP P A.Super-enhancer-mediated RNA processing revealed by integrative MicroRNA network analysis[J].Cell, 2017, 168(6):1000-1014.e15.
[42]	NG R, HUSSAIN N A, ZHANG Q Y, et al.miRNA-32 Drives brown fat thermogenesis and trans-activates subcutaneous white fat browning in Mice[J].Cell Rep, 2017, 19(6):1229-1246.
[43]	SIN-CHAN P, MUMAL I, SUWAL T, et al.A C19MC-LIN28A-MYCN oncogenic circuit driven by hijacked super-enhancers is a distinct therapeutic vulnerability in ETMRs:a lethal brain tumor[J].Cancer Cell, 2019, 36(1):51-67.e7.
[44]	ANANDAGODA N, WILLIS J C D, HERTWECK A, et al.microRNA-142-mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance[J].J Clin Invest, 2019, 129(3):1257-1271.
[45]	PEFANIS E, WANG J G, ROTHSCHILD G, et al.RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity[J].Cell, 2015, 161(4):774-789.
[46]	SOIBAM B.Super-lncRNAs:identification of lncRNAs that target super-enhancers via RNA:DNA:DNA triplex formation[J].RNA, 2017, 23(11):1729-1742.
[47]	ANDERSON K M, ANDERSON D M, MCANALLY J R, et al.Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development[J].Nature, 2016, 539(7629):433-436.
[48]	ZHOU C, YORK S R, CHEN J Y, et al.Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins[J].Genome Med, 2016, 8(1):31.
[49]	FAN Z H, ZHAO M, JOSHI P D, et al.A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation[J].Nucleic Acids Res, 2017, 45(10):5720-5738.
[50]	TANG Z D, LI X C, ZHAO J M, et al.TRCirc:a resource for transcriptional regulation information of circRNAs[J].Brief Bioinform, 2019, 20(6):2327-2333.
[51]	HAN J X, MENG J, CHEN S, et al.YY1 Complex promotes quaking expression via super-enhancer binding during EMT of hepatocellular carcinoma[J].Cancer Res, 2019, 79(7):1451-1464.
[52]	HUANG S L, LI X Z, ZHENG H, et al.Loss of super-enhancer-regulated circRNA nfix induces cardiac regeneration after myocardial infarction in adult mice[J].Circulation, 2019, 139(25):2857-2876.
[53]	BLINKA S, REIMER M H JR, PULAKANTI K, et al.Super-enhancers at the Nanog locus differentially regulate neighboring pluripotency-associated genes[J].Cell Rep, 2016, 17(1):19-28.
[54]	OUNZAIN S, MICHELETTI R, ARNAN C, et al.CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis[J].J Mol Cell Cardiol, 2015, 89:98-112.
[55]	CICHEWICZ M A, KIRAN M, PRZANOWSKA R K, et al.MUNC, an enhancer RNA upstream from the MYOD Gene, induces a subgroup of myogenic transcripts in trans independently of MyoD[J].Mol Cell Biol, 2018, 38(20):e00655-17.
[56]	TAN Y, LI Y J, TANG F Q.Oncogenic seRNA functional activation:a novel mechanism of tumorigenesis[J]. Mol Cancer, 2020, 19(1):74.
[57]	BRANGWYNNE C P, ECKMANN C R, COURSON D S, et al.Germline P granules are liquid droplets that localize by controlled dissolution/condensation[J]. Science, 2009, 324(5935):1729-1732.
[58]	BRANGWYNNE C P, MITCHISON T J, HYMAN A A.Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes[J].Proc Natl Acad Sci USA, 2011, 108(11):4334-4339.
[59]	GUO L, KIM H J, WANG H J, et al.Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains[J].Cell, 2018, 173(3):677-692.e20.
[60]	KILIC S, LEZAJA A, GATTI M, et al.Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments[J].EMBO J, 2019, 38(16):e101379.
[61]	MILOVANOVIC D, WU Y M, BIAN X, et al.A liquid phase of synapsin and lipid vesicles[J]. Science, 2018, 361(6402):604-607.
[62]	HNISZ D, SHRINIVAS K, YOUNG R A, et al.A phase separation model for transcriptional control[J].Cell, 2017, 169(1):13-23.
[63]	SABARI B R, DALL'AGNESE A, BOIJA A, et al.Coactivator condensation at super-enhancers links phase separation and gene control[J].Science, 2018, 361(6400):eaar3958.
[64]	BOIJA A, KLEIN I A, SABARI B R, et al.Transcription factors activate genes through the phase-separation capacity of their activation domains[J].Cell, 2018, 175(7):1842-1855.e16.
[65]	ZHU X L, ZHANG T T, ZHANG Y, et al.A super-enhancer controls TGF-β signaling in pancreatic cancer through downregulation of TGFBR2[J].Cell Signal, 2020, 66:109470.
[66]	GALLI G G, CARRARA M, YUAN W C, et al.YAP drives growth by controlling transcriptional pause release from dynamic enhancers[J].Mol Cell, 2015, 60(2):328-337.
[67]	SUN X, REN Z J, CUN Y X, et al.Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers[J].Nucleic Acids Res, 2020, 48(13):7182-7196.
[68]	ZHANG J Q, YUE W, ZHOU Y Q, et al.Super enhancers-Functional cores under the 3D genome[J]. Cell Prolif, 2021, 54(2):e12970.
[69]	SHIN H Y, HENNIGHAUSEN L, YOO K H.STAT5-driven enhancers tightly control temporal expression of mammary-specific genes[J].J Mammary Gland Biol Neoplasia, 2019, 24(1):61-71.
[70]	ZHAO Y, ZHOU J J, HE L Q, et al.MyoD induced enhancer RNA interacts with hnRNPL to activate target gene transcription during myogenic differentiation[J].Nat Commun, 2019, 10(1):5787.
[71]	ZHANG N, MENDIETA-ESTEBAN J, MAGLI A, et al.Muscle progenitor specification and myogenic differentiation are associated with changes in chromatin topology[J].Nat Commun, 2020, 11(1):6222.
[72]	LAI B B, LEE J E, JANG Y, et al.MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis[J].Nucleic Acids Res, 2017, 45(11):6388-6403.
[73]	BROWN J D, FELDMAN Z B, DOHERTY S P, et al.BET bromodomain proteins regulate enhancer function during adipogenesis[J].Proc Natl Acad Sci USA, 2018, 115(9):2144-2149.
[74]	SYAFRUDDIN S E, RODRIGUES P, VOJTASOVA E, et al.A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma[J].Nat Commun, 2019, 10(1):1152.
[75]	LUAN Y, ZHANG L, HU M Y, et al.Identification and conservation analysis of Cis-regulatory elements in pig liver[J].Genes, 2019, 10(5):348.
[76]	PÉREZ-RICO Y A, BOEVA V, MALLORY A C, et al.Comparative analyses of super-enhancers reveal conserved elements in vertebrate genomes[J].Genome Res, 2017, 27(2):259-268.
[77]	CHEN C G, ZHOU D S, GU Y, et al.SEA version 3.0:a comprehensive extension and update of the Super-Enhancer archive[J].Nucleic Acids Res, 2020, 48(D1):D198-D203.
[78]	MI Z Y, SONG Y D, CAO X Y, et al.Super-enhancer-driven metabolic reprogramming promotes cystogenesis in autosomal dominant polycystic kidney disease[J].Nat Metab, 2020, 2(8):717-731.
[79]	王晶晶, 张培培, 郝海生, 等.牛体内囊胚全转录组模式解析[J].畜牧兽医学报, 2020, 51(6):1271-1280.WANG J J, ZHANG P P, HAO H S, et al.Analysis of whole transcriptome pattern of bovine in vivo blastocyst[J].Acta Veterinaria et Zootechnica Sinica, 2020, 51(6):1271-1280.(in Chinese)
[80]	王欢, 邹惠影, 朱化彬, 等.CRISPR/Cas9基因编辑技术在家畜育种新材料创制中的研究进展[J].畜牧兽医学报, 2021, 52(4):851-861.WANG H, ZOU H Y, ZHU H B, et al.Advances in evaluation of livestock breeding new materials by using the CRISPR/Cas9 gene editing technology[J].Acta Veterinaria et Zootechnica Sinica, 2021, 52(4):851-861.(in Chinese)