The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MicroRNAs

English version České info

The transcriptome, as the pool of all transcribed elements in a given cell, is regulated by the interaction between different molecular levels, involving epigenetic, transcriptional, and post-transcriptional mechanisms. However, many previous studies investigated each of these levels individually, and little is known about their interdependency. We present a systems biology study integrating mRNA profiles with DNA–binding events of key cardiac transcription factors (Gata4, Mef2a, Nkx2.5, and Srf), activating histone modifications (H3ac, H4ac, H3K4me2, and H3K4me3), and microRNA profiles obtained in wild-type and RNAi–mediated knockdown. Finally, we confirmed conclusions primarily obtained in cardiomyocyte cell culture in a time-course of cardiac maturation in mouse around birth. We provide insights into the combinatorial regulation by cardiac transcription factors and show that they can partially compensate each other's function. Genes regulated by multiple transcription factors are less likely differentially expressed in RNAi knockdown of one respective factor. In addition to the analysis of the individual transcription factors, we found that histone 3 acetylation correlates with Srf- and Gata4-dependent gene expression and is complementarily reduced in cardiac Srf knockdown. Further, we found that altered microRNA expression in Srf knockdown potentially explains up to 45% of indirect mRNA targets. Considering all three levels of regulation, we present an Srf-centered transcription network providing on a single-gene level insights into the regulatory circuits establishing respective mRNA profiles. In summary, we show the combinatorial contribution of four DNA–binding transcription factors in regulating the cardiac transcriptome and provide evidence that histone modifications and microRNAs modulate their functional consequence. This opens a new perspective to understand heart development and the complexity cardiovascular disorders.

Vyšlo v časopise: The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MicroRNAs. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001313
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001313

Souhrn

Zdroje

1. MolkentinJD

LinQ

DuncanSA

OlsonEN

1997 Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 11 1061 1072

2. KuoCT

MorriseyEE

AnandappaR

SigristK

LuMM

1997 GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11 1048 1060

3. LyonsI

ParsonsLM

HartleyL

LiR

AndrewsJE

1995 Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9 1654 1666

4. NayaF

BlackB

WuH

Bassel-DubyR

RichardsonJ

2002 Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nat Med 8 1303 1309

5. NiuZ

YuW

ZhangSX

BarronM

BelaguliNS

2005 Conditional mutagenesis of the murine serum response factor gene blocks cardiogenesis and the transcription of downstream gene targets. J Biol Chem 280 32531 32538

6. MianoJM

RamananN

GeorgerMA

de Mesy BentleyKL

EmersonRL

2004 Restricted inactivation of serum response factor to the cardiovascular system. Proc Natl Acad Sci USA 101 17132 17137

7. BalzaROJr

MisraRP

2006 Role of the serum response factor in regulating contractile apparatus gene expression and sarcomeric integrity in cardiomyocytes. J Biol Chem 281 6498 6510

8. KaramboulasC

DakuboGD

LiuJ

De RepentignyY

YutzeyK

2006 Disruption of MEF2 activity in cardiomyoblasts inhibits cardiomyogenesis. J Cell Sci 119 4315 4321

9. SearcyRD

VincentEB

LiberatoreCM

YutzeyKE

1998 A GATA-dependent nkx-2.5 regulatory element activates early cardiac gene expression in transgenic mice. Development 125 4461 4470

10. SpencerJA

MisraRP

1996 Expression of the serum response factor gene is regulated by serum response factor binding sites. J Biol Chem 271 16535 16543

11. KouzaridesT

2007 Chromatin modifications and their function. Cell 128 693 705

12. RuthenburgAJ

LiH

PatelDJ

AllisCD

2007 Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8 983 994

13. LangeM

KaynakB

ForsterUB

TonjesM

FischerJJ

2008 Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex. Genes Dev 22 2370 2384

14. ThorneJL

CampbellMJ

TurnerBM

2009 Transcription factors, chromatin and cancer. Int J Biochem Cell Biol 41 164 175

15. WangZ

ZangC

CuiK

SchonesDE

BarskiA

2009 Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138 1019 1031

16. ChangS

McKinseyTA

ZhangCL

RichardsonJA

HillJA

2004 Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24 8467 8476

17. HaberlandM

MontgomeryRL

OlsonEN

2009 The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10 32 42

18. GitterA

SiegfriedZ

KlutsteinM

FornesO

OlivaB

2009 Backup in gene regulatory networks explains differences between binding and knockout results. Mol Syst Biol 5 276

19. YuM

RivaL

XieH

SchindlerY

MoranT

2009 Insights into GATA-1-Mediated Gene Activation versus Repression via Genome-wide Chromatin Occupancy Analysis. Molecular Cell 36 682 695

20. Phuc LeP

FriedmanJR

SchugJ

BrestelliJE

ParkerJB

2005 Glucocorticoid receptor-dependent gene regulatory networks. PLoS Genet 1 e16 doi:10.1371/journal.pgen.0010016

21. KwonY-S

Garcia-BassetsI

HuttKR

ChengCS

JinM

2007 Sensitive ChIP-DSL technology reveals an extensive estrogen receptor alpha-binding program on human gene promoters. Proc Natl Acad Sci USA 104 4852 4857

22. HuZ

KillionPJ

IyerVR

2007 Genetic reconstruction of a functional transcriptional regulatory network. Nat Genet 39 683 687

23. HarbisonC

GordonD

LeeT

RinaldiN

MacisaacK

2004 Transcriptional regulatory code of a eukaryotic genome. Nature 431 99 104

24. CordesKR

SheehyNT

WhiteMP

BerryEC

MortonSU

2009 miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460 705 710

25. KwonC

HanZ

OlsonEN

SrivastavaD

2005 MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proc Natl Acad Sci U S A 102 18986 18991

26. ChenJF

MandelEM

ThomsonJM

WuQ

CallisTE

2006 The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38 228 233

27. NiuZ

LiA

ZhangSX

SchwartzRJ

2007 Serum response factor micromanaging cardiogenesis. Curr Opin Cell Biol 19 618 627

28. ZhaoY

RansomJF

LiA

VedanthamV

von DrehleM

2007 Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129 303 317

29. KnuppelR

DietzeP

LehnbergW

FrechK

WingenderE

1994 TRANSFAC retrieval program: a network model database of eukaryotic transcription regulating sequences and proteins. J Comput Biol 1 191 198

30. MianoJM

LongX

FujiwaraK

2007 Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus. Am J Physiol Cell Physiol 292 C70 81

31. SiepelA

BejeranoG

PedersenJ

HinrichsA

HouM

2005 Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15 1034 1050

32. AkazawaH

KomuroI

2005 Cardiac transcription factor Csx/Nkx2-5: Its role in cardiac development and diseases. Pharmacol Ther 107 252 268

33. ClarkKL

YutzeyKE

BensonDW

2006 Transcription factors and congenital heart defects. Annual Review of Physiology 68 97 121

34. KobayashiS

LackeyT

HuangY

BispingE

PuWT

2006 Transcription factor gata4 regulates cardiac BCL2 gene expression in vitro and in vivo. Faseb J 20 800 802

35. VickersER

KaszaA

KurnazIA

SeifertA

ZeefLAH

2004 Ternary complex factor-serum response factor complex-regulated gene activity is required for cellular proliferation and inhibition of apoptotic cell death. Mol Cell Biol 24 10340 10351

36. SuzukiYJ

EvansT

2004 Regulation of cardiac myocyte apoptosis by the GATA-4 transcription factor. Life Sci 74 1829 1838

37. BruneauBG

NemerG

SchmittJP

CharronF

RobitailleL

2001 A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106 709 721

38. PuWT

IshiwataT

JuraszekAL

MaQ

IzumoS

2004 GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Developmental Biology 275 235 244

39. FischerJJ

ToedlingJ

KruegerT

SchuelerM

HuberW

2008 Combinatorial effects of four histone modifications in transcription and differentiation. Genomics 91 41 51

40. TakayaT

KawamuraT

MorimotoT

OnoK

KitaT

2008 Identification of p300-targeted acetylated residues in GATA4 during hypertrophic responses in cardiac myocytes. J Biol Chem 283 9828 9835

41. CaoD

WangZ

ZhangCL

OhJ

XingW

2005 Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin. Mol Cell Biol 25 364 376

42. HirschyA

SchatzmannF

EhlerE

PerriardJC

2006 Establishment of cardiac cytoarchitecture in the developing mouse heart. Dev Biol 289 430 441

43. van RooijE

LiuN

OlsonEN

2008 MicroRNAs flex their muscles. Trends Genet 24 159 166

44. LatronicoMV

CatalucciD

CondorelliG

2008 MicroRNA and cardiac pathologies. Physiol Genomics 34 239 242

45. KelAE

GosslingE

ReuterI

CheremushkinE

Kel-MargoulisOV

2003 MATCH: A tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res 31 3576 3579

46. ENCODE 2007 Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447 799 816

47. FarnhamPJ

2009 Insights from genomic profiling of transcription factors. Nat Rev Genet 10 605 616

48. VaquerizasJM

KummerfeldSK

TeichmannSA

LuscombeNM

2009 A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10 252 263

49. KochCM

AndrewsRM

FlicekP

DillonSC

KaraözU

2007 The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res 17 691 707

50. WangY

LiangY

LuQ

2008 MicroRNA epigenetic alterations: predicting biomarkers and therapeutic targets in human diseases. Clin Genet 74 307 315

51. CordesKR

SrivastavaD

2009 MicroRNA regulation of cardiovascular development. Circ Res 104 724 732

52. BonauerA

CarmonaG

IwasakiM

MioneM

KoyanagiM

2009 MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324 1710 1713

53. KimVN

HanJ

SiomiMC

2009 Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10 126 139

54. LinQ

SchwarzJ

BucanaC

OlsonEN

1997 Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276 1404 1407

55. VongLH

RagusaMJ

SchwarzJJ

2005 Generation of conditional Mef2cloxP/loxP mice for temporal- and tissue-specific analyses. Genesis 43 43 48

56. SperlingS

GrimmCH

DunkelI

MebusS

SperlingHP

2005 Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Hum Mutat 26 575 582

57. MacDonaldST

BamforthSD

ChenC-M

FarthingCR

FranklynA

2008 Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency. Cardiovasc Res 79 448 457

58. McGeeS

FairlieE

GarnhamA

HargreavesM

2009 Exercise-induced histone modifications in human skeletal muscle. J Physiol (Lond)

59. SaccaniS

PantanoS

NatoliG

2002 p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 3 69 75

60. SripichaiO

KieferCM

BhanuNV

TannoT

NohS-J

2009 Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming. Blood 114 2299 2306

61. ShalgiR

LieberD

OrenM

PilpelY

2007 Global and local architecture of the mammalian microRNA-transcription factor regulatory network. PLoS Comput Biol 3 e131 doi:10.1371/journal.pcbi.0030131

62. SiomiH

SiomiMC

2009 On the road to reading the RNA-interference code. Nature 457 396 404

63. ToenjesM

SchuelerM

HammerS

PapeUJ

FischerJJ

2008 Prediction of cardiac transcription networks based on molecular data and complex clinical phenotypes. Mol Biosyst 4 589 598

64. ClaycombWC

LansonNAJr

StallworthBS

EgelandDB

DelcarpioJB

1998 HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci U S A 95 2979 2984

65. SmythGK

2004 Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3 Article3

66. GentlemanRC

CareyVJ

BatesDM

BolstadB

DettlingM

2004 Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5 R80

67. BenjaminiY

YekutieliD

2001 The control of the false discovery rate in multiple testing under dependency. Annals of Statistics 29 1165 1188

68. ChenC

RidzonDA

BroomerAJ

ZhouZ

LeeDH

2005 Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33 e179

69. WuRM

WoodM

ThrushA

WaltonEF

Varkonyi-GasicE

2007 Real-Time PCR Quantification of Plant miRNAs Using Universal ProbeLibrary Technology. Biochemica 2

70. EmdeAK

GrunertM

WeeseD

ReinertK

SperlingSR

2009 MicroRazerS: rapid alignment of small RNA reads. Bioinformatics 26 123 124

71. JohnB

EnrightAJ

AravinA

TuschlT

SanderC

2004 Human MicroRNA targets. PLoS Biol 2 e363 doi:10.1371/journal.pbio.0020363

72. HorakCE

MahajanMC

LuscombeNM

GersteinM

WeissmanSM

2002 GATA-1 binding sites mapped in the beta-globin locus by using mammalian chIp-chip analysis. Proc Natl Acad Sci U S A 99 2924 2929

73. HuberW

von HeydebreckA

SultmannH

PoustkaA

VingronM

2002 Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18 Suppl 1 S96 104

74. StoreyJD

TibshiraniR

2003 Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 9440 9445

75. WeeseD

EmdeAK

RauschT

DoringA

ReinertK

2009 RazerS–fast read mapping with sensitivity control. Genome Res 19 1646 1654

76. JiH

JiangH

MaW

JohnsonDS

MyersRM

2008 An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nat Biotechnol 26 1293 1300

77. AshburnerM

BallCA

BlakeJA

BotsteinD

ButlerH

2000 Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25 25 29

78. AlexaA

RahnenfuhrerJ

LengauerT

2006 Improved scoring of functional groups from gene expression data by decorrelating GO graph structure. Bioinformatics 22 1600 1607

79. AndersonC

CatoeH

WernerR

2006 MIR-206 regulates connexin43 expression during skeletal muscle development. Nucleic Acids Res 34 5863 5871

80. BoutzPL

ChawlaG

StoilovP

BlackDL

2007 MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development. Genes Dev 21 71 84

81. CallisTE

DengZ

ChenJF

WangDZ

2008 Muscling through the microRNA world. Exp Biol Med (Maywood) 233 131 138

82. CareA

CatalucciD

FelicettiF

BonciD

AddarioA

2007 MicroRNA-133 controls cardiac hypertrophy. Nat Med 13 613 618

83. ChenCZ

LiL

LodishHF

BartelDP

2004 MicroRNAs modulate hematopoietic lineage differentiation. Science 303 83 86

84. ChengAM

ByromMW

SheltonJ

FordLP

2005 Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 33 1290 1297

85. CimminoA

CalinGA

FabbriM

IorioMV

FerracinM

2005 miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102 13944 13949

86. ClopA

MarcqF

TakedaH

PirottinD

TordoirX

2006 A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38 813 818

87. FanGC

ChuG

KraniasEG

2005 Hsp20 and its cardioprotection. Trends Cardiovasc Med 15 138 141

88. FelliN

FontanaL

PelosiE

BottaR

BonciD

2005 MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci U S A 102 18081 18086

89. KimHK

LeeYS

SivaprasadU

MalhotraA

DuttaA

2006 Muscle-specific microRNA miR-206 promotes muscle differentiation. J Cell Biol 174 677 687

90. KutayH

BaiS

DattaJ

MotiwalaT

PogribnyI

2006 Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem 99 671 678

91. Lagos-QuintanaM

RauhutR

MeyerJ

BorkhardtA

TuschlT

2003 New microRNAs from mouse and human. Rna 9 175 179

92. LalA

NavarroF

MaherCA

MaliszewskiLE

YanN

2009 miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to “seedless” 3′UTR microRNA recognition elements. Mol Cell 35 610 625

93. LatronicoMV

CatalucciD

CondorelliG

2007 Emerging role of microRNAs in cardiovascular biology. Circ Res 101 1225 1236

94. LuoX

LinH

PanZ

XiaoJ

ZhangY

2008 Down-regulation of miR-1/miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart. J Biol Chem 283 20045 20052

95. MarsonA

LevineSS

ColeMF

FramptonGM

BrambrinkT

2008 Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134 521 533

96. McCarthyJJ

EsserKA

2007 MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy. J Appl Physiol 102 306 313

97. MengF

HensonR

Wehbe-JanekH

GhoshalK

JacobST

2007 MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer Gastroenterology 647 658

98. MottJL

KobayashiS

BronkSF

GoresGJ

2007 mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26 6133 6140

99. NaguibnevaI

Ameyar-ZazouaM

PolesskayaA

Ait-Si-AliS

GroismanR

2006 The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation. Nat Cell Biol 8 278 284

100. ParkSY

LeeJH

HaM

NamJW

KimVN

2009 miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol 16 23 29

101. PetroccaF

VisoneR

OnelliMR

ShahMH

NicolosoMS

2008 E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13 272 286

102. RaoPK

KumarRM

FarkhondehM

BaskervilleS

LodishHF

2006 Myogenic factors that regulate expression of muscle-specific microRNAs. Proc Natl Acad Sci U S A 103 8721 8726

103. RenXP

WuJ

WangX

SartorMA

QianJ

2009 MicroRNA-320 is involved in the regulation of cardiac ischemia/reperfusion injury by targeting heat-shock protein 20. Circulation 119 2357 2366

104. RosenbergMI

GeorgesSA

AsawachaicharnA

AnalauE

TapscottSJ

2006 MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206. J Cell Biol 175 77 85

105. SmirnovaL

GrafeA

SeilerA

SchumacherS

NitschR

2005 Regulation of miRNA expression during neural cell specification. Eur J Neurosci 21 1469 1477

106. TangY

ZhengJ

SunY

WuZ

LiuZ

2009 MicroRNA-1 regulates cardiomyocyte apoptosis by targeting Bcl-2. Int Heart J 50 377 387

107. ThumT

CatalucciD

BauersachsJ

2008 MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res 79 562 570

108. ThumT

GaluppoP

WolfC

FiedlerJ

KneitzS

2007 MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116 258 267

109. ThumT

GrossC

FiedlerJ

FischerT

KisslerS

2008 MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456 980 984

110. TiliE

MichailleJJ

CiminoA

CostineanS

DumitruCD

2007 Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179 5082 5089

111. TuddenhamL

WheelerG

Ntounia-FousaraS

WatersJ

HajihosseiniMK

2006 The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Lett 580 4214 4217

112. UrbichC

KuehbacherA

DimmelerS

2008 Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res 79 581 588

113. van RooijE

SutherlandLB

QiX

RichardsonJA

HillJ

2007 Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316 575 579

114. XiaoJ

LuoX

LinH

ZhangY

LuY

2007 MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts. J Biol Chem 282 12363 12367

115. XuC

LuY

PanZ

ChuW

LuoX

2007 The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. J Cell Sci 120 3045 3052

116. YangB

LinH

XiaoJ

LuY

LuoX

2007 The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med 13 486 491

117. YuasaK

HagiwaraY

AndoM

NakamuraA

TakedaS

2008 MicroRNA-206 is highly expressed in newly formed muscle fibers: implications regarding potential for muscle regeneration and maturation in muscular dystrophy. Cell Struct Funct 33 163 169

118. ZhaoY

SamalE

SrivastavaD

2005 Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436 214 220

119. ZhuS

SiML

WuH

MoYY

2007 MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282 14328 14336

120. ZhuS

WuH

WuF