Combinatorial Binding Leads to Diverse Regulatory Responses: Lmd Is a Tissue-Specific Modulator of Mef2 Activity

English version České info

Understanding how complex patterns of temporal and spatial expression are regulated is central to deciphering genetic programs that drive development. Gene expression is initiated through the action of transcription factors and their cofactors converging on enhancer elements leading to a defined activity. Specific constellations of combinatorial occupancy are therefore often conceptualized as rigid binding codes that give rise to a common output of spatio-temporal expression. Here, we assessed this assumption using the regulatory input of two essential transcription factors within the Drosophila myogenic network. Mutations in either Myocyte enhancing factor 2 (Mef2) or the zinc-finger transcription factor lame duck (lmd) lead to very similar defects in myoblast fusion, yet the underlying molecular mechanism for this shared phenotype is not understood. Using a combination of ChIP-on-chip analysis and expression profiling of loss-of-function mutants, we obtained a global view of the regulatory input of both factors during development. The majority of Lmd-bound enhancers are co-bound by Mef2, representing a subset of Mef2's transcriptional input during these stages of development. Systematic analyses of the regulatory contribution of both factors demonstrate diverse regulatory roles, despite their co-occupancy of shared enhancer elements. These results indicate that Lmd is a tissue-specific modulator of Mef2 activity, acting as both a transcriptional activator and repressor, which has important implications for myogenesis. More generally, this study demonstrates considerable flexibility in the regulatory output of two factors, leading to additive, cooperative, and repressive modes of co-regulation.

Vyšlo v časopise: Combinatorial Binding Leads to Diverse Regulatory Responses: Lmd Is a Tissue-Specific Modulator of Mef2 Activity. PLoS Genet 6(7): e32767. doi:10.1371/journal.pgen.1001014
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001014

Souhrn

Zdroje

1. BonnS

FurlongEE

2008 cis-Regulatory networks during development: a view of Drosophila. Curr Opin Genet Dev 18 513 520

2. BourBA

O'BrienMA

LockwoodWL

GoldsteinES

BodmerR

1995 Drosophila MEF2, a transcription factor that is essential for myogenesis. Genes Dev 9 730 741

3. DuanH

SkeathJB

NguyenHT

2001 Drosophila Lame duck, a novel member of the Gli superfamily, acts as a key regulator of myogenesis by controlling fusion-competent myoblast development. Development 128 4489 4500

4. Ruiz-GomezM

CouttsN

SusterML

LandgrafM

BateM

2002 myoblasts incompetent encodes a zinc finger transcription factor required to specify fusion-competent myoblasts in Drosophila. Development 129 133 141

5. PotthoffMJ

OlsonEN

2007 MEF2: a central regulator of diverse developmental programs. Development 134 4131 4140

6. MolkentinJD

BlackBL

MartinJF

OlsonEN

1995 Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell 83 1125 1136

7. PennBH

BergstromDA

DilworthFJ

BengalE

TapscottSJ

2004 A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation. Genes Dev 18 2348 2353

8. VerziMP

AgarwalP

BrownC

McCulleyDJ

SchwarzJJ

2007 The transcription factor MEF2C is required for craniofacial development. Dev Cell 12 645 652

9. MillerCT

SwartzME

KhuuPA

WalkerMB

EberhartJK

2007 mef2ca is required in cranial neural crest to effect Endothelin1 signaling in zebrafish. Dev Biol 308 144 157

10. WangZ

WangDZ

PipesGC

OlsonEN

2003 Myocardin is a master regulator of smooth muscle gene expression. Proc Natl Acad Sci U S A 100 7129 7134

11. SandmannT

JensenLJ

JakobsenJS

KarzynskiMM

EichenlaubMP

2006 A temporal map of transcription factor activity: mef2 directly regulates target genes at all stages of muscle development. Dev Cell 10 797 807

12. JunionG

JaglaT

DuplantS

TapinR

Da PonteJP

2005 Mapping Dmef2-binding regulatory modules by using a ChIP-enriched in silico targets approach. Proc Natl Acad Sci U S A 102 18479 18484

13. ElgarSJ

HanJ

TaylorMV

2008 mef2 activity levels differentially affect gene expression during Drosophila muscle development. Proc Natl Acad Sci U S A 105 918 923

14. LiottaD

HanJ

ElgarS

GarveyC

HanZ

2007 The Him gene reveals a balance of inputs controlling muscle differentiation in Drosophila. Curr Biol 17 1409 1413

15. BayliesMK

MichelsonAM

2001 Invertebrate myogenesis: looking back to the future of muscle development. Curr Opin Genet Dev 11 431 439

16. FurlongEE

AndersenEC

NullB

WhiteKP

ScottMP

2001 Patterns of gene expression during Drosophila mesoderm development. Science 293 1629 1633

17. SellinJ

DrechslerM

NguyenHT

PaululatA

2009 Antagonistic function of Lmd and Zfh1 fine tunes cell fate decisions in the Twi and Tin positive mesoderm of Drosophila melanogaster. Dev Biol 326 444 455

18. StuteC

2004 The determination of the founder and fusion competent myoblasts of the visceral mesoderm of Drosophila melanogaster depends on Notch as well as on Jeb/Alk mediated RTK-signalling. Marburg Universität Marburg

19. HinzU

WolkA

Renkawitz-PohlR

1992 Ultrabithorax is a regulator of beta 3 tubulin expression in the Drosophila visceral mesoderm. Development 116 543 554

20. KellyKK

MeadowsSM

CrippsRM

2002 Drosophila MEF2 is a direct regulator of Actin57B transcription in cardiac, skeletal, and visceral muscle lineages. Mech Dev 110 39 50

21. TomancakP

BeatonA

WeiszmannR

KwanE

ShuS

2002 Systematic determination of patterns of gene expression during Drosophila embryogenesis. Genome Biol 3 RESEARCH0088

22. BrandAH

PerrimonN

1993 Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118 401 415

23. BourBA

ChakravartiM

WestJM

AbmayrSM

2000 Drosophila SNS, a member of the immunoglobulin superfamily that is essential for myoblast fusion. Genes Dev 14 1498 1511

24. DammC

WolkA

ButtgereitD

LoherK

WagnerE

1998 Independent regulatory elements in the upstream region of the Drosophila beta 3 tubulin gene (beta Tub60D) guide expression in the dorsal vessel and the somatic muscles. Dev Biol 199 138 149

25. KremserT

GajewskiK

SchulzRA

Renkawitz-PohlR

1999 Tinman regulates the transcription of the beta3 tubulin gene (betaTub60D) in the dorsal vessel of Drosophila. Dev Biol 216 327 339

26. JakobsenJS

BraunM

AstorgaJ

GustafsonEH

SandmannT

2007 Temporal ChIP-on-chip reveals Biniou as a universal regulator of the visceral muscle transcriptional network. Genes Dev 21 2448 2460

27. SimsD

BursteinasB

GaoQ

ZvelebilM

BaumB

2006 FLIGHT: database and tools for the integration and cross-correlation of large-scale RNAi phenotypic datasets. Nucleic Acids Res 34 D479 483

28. PavesiG

MereghettiP

MauriG

PesoleG

2004 Weeder Web: discovery of transcription factor binding sites in a set of sequences from co-regulated genes. Nucleic Acids Res 32 W199 203

29. Ho SuiSJ

FultonDL

ArenillasDJ

KwonAT

WassermanWW

2007 oPOSSUM: integrated tools for analysis of regulatory motif over-representation. Nucleic Acids Res 35 W245 252

30. CliftenP

SudarsanamP

DesikanA

FultonL

FultonB

2003 Finding functional features in Saccharomyces genomes by phylogenetic footprinting. Science 301 71 76

31. AertsS

ThijsG

CoessensB

StaesM

MoreauY

2003 Toucan: deciphering the cis-regulatory logic of coregulated genes. Nucleic Acids Res 31 1753 1764

32. GelfandMS

NovichkovPS

NovichkovaES

MironovAA

2000 Comparative analysis of regulatory patterns in bacterial genomes. Brief Bioinform 1 357 371

33. GrayS

CaiH

BaroloS

LevineM

1995 Transcriptional repression in the Drosophila embryo. Philos Trans R Soc Lond B Biol Sci 349 257 262

34. GrayS

LevineM

1996 Short-range transcriptional repressors mediate both quenching and direct repression within complex loci in Drosophila. Genes Dev 10 700 710

35. SandmannT

JakobsenJS

FurlongEE

2006 ChIP-on-chip protocol for genome-wide analysis of transcription factor binding in Drosophila melanogaster embryos. Nat Protoc 1 2839 2855

36. FurlongEE

ProfittD

ScottMP

2001 Automated sorting of live transgenic embryos. Nat Biotechnol 19 153 156

37. TusherVG

TibshiraniR

ChuG

2001 Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98 5116 5121

38. BreitlingR

ArmengaudP

AmtmannA

HerzykP

2004 Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments. FEBS Lett 573 83 92

39. BaroloS

CarverLA

PosakonyJW

2000 GFP and beta-galactosidase transformation vectors for promoter/enhancer analysis in Drosophila. Biotechniques 29 726, 728, 730, 732