#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Transcriptional Regulation by CHIP/LDB Complexes


It is increasingly clear that transcription factors play versatile roles in turning genes “on” or “off” depending on cellular context via the various transcription complexes they form. This poses a major challenge in unraveling combinatorial transcription complex codes. Here we use the powerful genetics of Drosophila combined with microarray and bioinformatics analyses to tackle this challenge. The nuclear adaptor CHIP/LDB is a major developmental regulator capable of forming tissue-specific transcription complexes with various types of transcription factors and cofactors, making it a valuable model to study the intricacies of gene regulation. To date only few CHIP/LDB complexes target genes have been identified, and possible tissue-dependent crosstalk between these complexes has not been rigorously explored. SSDP proteins protect CHIP/LDB complexes from proteasome dependent degradation and are rate-limiting cofactors for these complexes. By using mutations in SSDP, we identified 189 down-stream targets of CHIP/LDB and show that these genes are enriched for the binding sites of APTEROUS (AP) and PANNIER (PNR), two well studied transcription factors associated with CHIP/LDB complexes. We performed extensive genetic screens and identified target genes that genetically interact with components of CHIP/LDB complexes in directing the development of the wings (28 genes) and thoracic bristles (23 genes). Moreover, by in vivo RNAi silencing we uncovered novel roles for two of the target genes, xbp1 and Gs-alpha, in early development of these structures. Taken together, our results suggest that loss of SSDP disrupts the normal balance between the CHIP-AP and the CHIP-PNR transcription complexes, resulting in down-regulation of CHIP-AP target genes and the concomitant up-regulation of CHIP-PNR target genes. Understanding the combinatorial nature of transcription complexes as presented here is crucial to the study of transcription regulation of gene batteries required for development.


Vyšlo v časopise: Transcriptional Regulation by CHIP/LDB Complexes. PLoS Genet 6(8): e32767. doi:10.1371/journal.pgen.1001063
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001063

Souhrn

It is increasingly clear that transcription factors play versatile roles in turning genes “on” or “off” depending on cellular context via the various transcription complexes they form. This poses a major challenge in unraveling combinatorial transcription complex codes. Here we use the powerful genetics of Drosophila combined with microarray and bioinformatics analyses to tackle this challenge. The nuclear adaptor CHIP/LDB is a major developmental regulator capable of forming tissue-specific transcription complexes with various types of transcription factors and cofactors, making it a valuable model to study the intricacies of gene regulation. To date only few CHIP/LDB complexes target genes have been identified, and possible tissue-dependent crosstalk between these complexes has not been rigorously explored. SSDP proteins protect CHIP/LDB complexes from proteasome dependent degradation and are rate-limiting cofactors for these complexes. By using mutations in SSDP, we identified 189 down-stream targets of CHIP/LDB and show that these genes are enriched for the binding sites of APTEROUS (AP) and PANNIER (PNR), two well studied transcription factors associated with CHIP/LDB complexes. We performed extensive genetic screens and identified target genes that genetically interact with components of CHIP/LDB complexes in directing the development of the wings (28 genes) and thoracic bristles (23 genes). Moreover, by in vivo RNAi silencing we uncovered novel roles for two of the target genes, xbp1 and Gs-alpha, in early development of these structures. Taken together, our results suggest that loss of SSDP disrupts the normal balance between the CHIP-AP and the CHIP-PNR transcription complexes, resulting in down-regulation of CHIP-AP target genes and the concomitant up-regulation of CHIP-PNR target genes. Understanding the combinatorial nature of transcription complexes as presented here is crucial to the study of transcription regulation of gene batteries required for development.


Zdroje

1. AlvarezM

RhodesSJ

BidwellJP

2003 Context-dependent transcription: all politics is local. Gene 313 43 57

2. RosenfeldMG

LunyakVV

GlassCK

2006 Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes & Development 20 1405 1428

3. MaJ

2005 Crossing the line between activation and repression. Trends Genet 21 54 59

4. MatthewsJM

VisvaderJE

2003 LIM-domain-binding protein 1: a multifunctional cofactor that interacts with diverse proteins. EMBO Rep 4 1132 1137

5. CohenB

McGuffinME

PfeifleC

SegalD

CohenSM

1992 apterous, a gene required for imaginal disc development in Drosophila encodes a member of the LIM family of developmental regulatory proteins. Genes & Development 6 715 729

6. Rincon-LimasDE

LuC-H

CanalI

CallejaM

Rodriguez-EstebanCn

1999 Conservation of the expression and function of apterous orthologs in Drosophila and mammals. Proceedings of the National Academy of Sciences of the United States of America 96 2165 2170

7. van MeyelDJ

O'KeefeDD

JurataLW

ThorS

GillGN

1999 Chip and Apterous Physically Interact to Form a Functional Complex during Drosophila Development. Molecular Cell 4 259 265

8. MilanM

CohenSM

1999 Regulation of LIM homeodomain activity in vivo: a tetramer of dLDB and apterous confers activity and capacity for regulation by dLMO. Mol Cell 4 267 273

9. MilanM

Diaz-BenjumeaFJ

CohenSM

1998 Beadex encodes an LMO protein that regulates Apterous LIM-homeodomain activity in Drosophila wing development: a model for LMO oncogene function. Genes Dev 12 2912 2920

10. van MeyelDJ

ThomasJB

AgulnickAD

2003 Ssdp proteins bind to LIM-interacting co-factors and regulate the activity of LIM-homeodomain protein complexes in vivo. Development 130 1915 1925

11. HerranzH

MilanM

2006 Notch and affinity boundaries in Drosophila. Bioessays 28 113 116

12. ShoreshM

OrgadS

ShmueliO

WerczbergerR

GelbaumD

1998 Overexpression Beadex mutations and loss-of-function heldup-a mutations in Drosophila affect the 3′ regulatory and coding components, respectively, of the Dlmo gene. Genetics 150 283 299

13. ChenL

SegalD

HukriedeNA

PodtelejnikovAV

BayarsaihanD

2002 Ssdp proteins interact with the LIM-domain-binding protein Ldb1 to regulate development. Proc Natl Acad Sci U S A 99 14320 14325

14. WeiheU

MilanM

CohenSM

2001 Regulation of Apterous activity in Drosophila wing development. Development 128 4615 4622

15. MilanM

CohenSM

2000 Temporal regulation of apterous activity during development of the Drosophila wing. Development 127 3069 3078

16. RamainP

KhechumianR

KhechumianK

ArbogastN

AckermannC

2000 Interactions between chip and the achaete/scute-daughterless heterodimers are required for pannier-driven proneural patterning. Mol Cell 6 781 790

17. RomaniS

CampuzanoS

MacagnoER

ModolellJ

1989 Expression of achaete and scute genes in Drosophila imaginal discs and their function in sensory organ development. Genes Dev 3 997 1007

18. ZenvirtS

Nevo-CaspiY

Rencus-LazarS

SegalD

2008 Drosophila LIM-only is a positive regulator of transcription during thoracic bristle development. Genetics 179 1989 1999

19. AsmarJ

BiryukovaI

HeitzlerP

2008 Drosophila dLMO-PA isoform acts as an early activator of achaete/scute proneural expression. Dev Biol 316 487 497

20. AgulnickAD

TairaM

BreenJJ

TanakaT

DawidIB

1996 Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature 384 270 272

21. NishiokaN

NaganoS

NakayamaR

KiyonariH

IjiriT

2005 Ssdp1 regulates head morphogenesis of mouse embryos by activating the Lim1-Ldb1 complex. Development 132 2535 2546

22. GungorC

Taniguchi-IshigakiN

MaH

DrungA

TursunB

2007 Proteasomal selection of multiprotein complexes recruited by LIM homeodomain transcription factors. Proc Natl Acad Sci U S A 104 15000 15005

23. OsadaH

GrutzG

AxelsonH

ForsterA

RabbittsTH

1995 Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proc Natl Acad Sci U S A 92 9585 9589

24. WadmanIA

OsadaH

GrutzGG

AgulnickAD

WestphalH

1997 The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. Embo J 16 3145 3157

25. XuZ

HuangS

ChangLS

AgulnickAD

BrandtSJ

2003 Identification of a TAL1 target gene reveals a positive role for the LIM domain-binding protein Ldb1 in erythroid gene expression and differentiation. Mol Cell Biol 23 7585 7599

26. CaiY

XuZ

NagarajanL

BrandtSJ

2008 Single-stranded DNA-binding proteins regulate the abundance and function of the LIM-homeodomain transcription factor LHX2 in pituitary cells. Biochem Biophys Res Commun 373 303 308

27. XuZ

MengX

CaiY

LiangH

NagarajanL

2007 Single-stranded DNA-binding proteins regulate the abundance of LIM domain and LIM domain-binding proteins. Genes Dev 21 942 955

28. ParisiM

NuttallR

NaimanD

BouffardG

MalleyJ

2003 Paucity of genes on the Drosophila X chromosome showing male-biased expression. Science 299 697 700

29. BayarsaihanD

SotoRJ

LukensLN

1998 Cloning and characterization of a novel sequence-specific single-stranded-DNA-binding protein. Biochem J 331 ( Pt2) 447 452

30. ElkonR

LinhartC

SharanR

ShamirR

ShilohY

2003 Genome-wide in silico identification of transcriptional regulators controlling the cell cycle in human cells. Genome Res 13 773 780

31. WingenderE

ChenX

HehlR

KarasH

LiebichI

2000 TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res 28 316 319

32. HaenlinM

CubaddaY

BlondeauF

HeitzlerP

LutzY

1997 Transcriptional activity of Pannier is regulated negatively by heterodimerization of the GATA DNA-binding domain with a cofactor encoded by the u-shaped gene of Drosophila. Genes & Development 11 3096 3108

33. GhaziA

PaulL

VijayRaghavanK

2003 Prepattern genes and signaling molecules regulate stripe expression to specify Drosophila flight muscle attachment sites. Mechanisms of Development 120 519 528

34. GhaziA

AnantS

VijayRaghavanK

2000 Apterous mediates development of direct flight muscles autonomously and indirect flight muscles through epidermal cues. Development 127 5309 5318

35. HeitzlerP

HaenlinM

RamainP

CallejaM

SimpsonP

1996 A genetic analysis of pannier, a gene necessary for viability of dorsal tissues and bristle positioning in Drosophila. Genetics 143 1271 1286

36. MorcilloP

RosenC

BayliesMK

DorsettD

1997 Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila. Genes Dev 11 2729 2740

37. Fernandez-FunezP

LuCH

Rincon-LimasDE

Garcia-BellidoA

BotasJ

1998 The relative expression amounts of apterous and its co-factor dLdb/Chip are critical for dorso-ventral compartmentalization in the Drosophila wing. Embo J 17 6846 6853

38. IrvineKD

WieschausE

1994 fringe, a Boundary-specific signaling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79 595 606

39. BlairSS

BrowerDL

ThomasJB

ZavortinkM

1994 The role of apterous in the control of dorsoventral compartmentalization and PS integrin gene expression in the developing wing of Drosophila. Development 120 1805 1815

40. BrandAH

PerrimonN

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

41. O'KeefeDD

ThorS

ThomasJB

1998 Function and specificity of LIM domains in Drosophila nervous system and wing development. Development 125 3915 3923

42. WuL

2006 Structure and functional characterization of single-strand DNA binding protein SSDP1: carboxyl-terminal of SSDP1 has transcription activity. Biochem Biophys Res Commun 339 977 984

43. BejaranoF

LuqueCM

HerranzH

SorrosalG

RafelN

2008 A gain-of-function suppressor screen for genes involved in dorsal-ventral boundary formation in the Drosophila wing. Genetics 178 307 323

44. OstendorffHP

PeiranoRI

PetersMA

SchluterA

BossenzM

2002 Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors. Nature 416 99 103

45. DejardinJ

CavalliG

2004 Chromatin inheritance upon Zeste-mediated Brahma recruitment at a minimal cellular memory module. Embo J 23 857 868

46. KalAJ

MahmoudiT

ZakNB

VerrijzerCP

2000 The Drosophila Brahma complex is an essential coactivator for the trithorax group protein Zeste. Genes & Development 14 1058 1071

47. HeitzlerP

VanolstL

BiryukovaI

RamainP

2003 Enhancer-promoter communication mediated by Chip during Pannier-driven proneural patterning is regulated by Osa. Genes & Development 17 591 596

48. MukherjeeT

SchaferU

ZeidlerMP

2006 Identification of Drosophila genes modulating janus kinase/signal transducer and activator of transcription signal transduction. Genetics 172 1683 1697

49. RamanaCV

GrammatikakisN

ChernovM

NguyenH

GohKC

2000 Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. Embo J 19 263 272

50. LiangH

SamantaS

NagarajanL

2005 SSBP2, a candidate tumor suppressor gene, induces growth arrest and differentiation of myeloid leukemia cells. Oncogene 24 2625 2634

51. LiuJ-W

NagpalJK

SunW

LeeJ

KimMS

2008 ssDNA-Binding Protein 2 Is Frequently Hypermethylated and Suppresses Cell Growth in Human Prostate Cancer. Clin Cancer Res 14 3754 3760

52. OtsuM

SitiaR

2007 Diseases Originating from Altered Protein Quality Control in the Endoplasmic Reticulum. Current Medicinal Chemistry 14 1639 1652

53. RyooHD

StellerH

2007 Unfolded protein response in Drosophila: why another model can make it fly. Cell Cycle 6 830 835

54. FurmanDP

BukharinaTA

2008 How Drosophila melanogaster Forms its Mechanoreceptors. Curr Genomics 9 312 323

55. LeeA-H

ScapaEF

CohenDE

GlimcherLH

2008 Regulation of Hepatic Lipogenesis by the Transcription Factor XBP1. Science 320 1492 1496

56. Acosta-AlvearD

ZhouY

BlaisA

TsikitisM

LentsNH

2007 XBP1 Controls Diverse Cell Type- and Condition-Specific Transcriptional Regulatory Networks. Molecular Cell 27 53 66

57. BourneHR

SandersDA

McCormickF

1991 The GTPase superfamily: conserved structure and molecular mechanism. Nature 349 117 127

58. KimuraK-i

KodamaA

HayasakaY

OhtaT

2004 Activation of the cAMP/PKA signaling pathway is required for post-ecdysial cell death in wing epidermal cells of Drosophila melanogaster. Development 131 1597 1606

59. KigerJAJr

NatzleJE

KimbrellDA

PaddyMR

KleinhesselinkK

2007 Tissue remodeling during maturation of the Drosophila wing. Developmental Biology 301 178 191

60. FabreCCG

CasalJ

LawrencePA

2008 The abdomen of Drosophila: does planar cell polarity orient the neurons of mechanosensory bristles? Neural Dev 3 12

61. DietzlG

ChenD

SchnorrerF

SuKC

BarinovaY

2007 A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448 151 156

62. RyderE

AshburnerM

Bautista-LlacerR

DrummondJ

WebsterJ

2007 The DrosDel Deletion Collection: A Drosophila Genomewide Chromosomal Deficiency Resource. Genetics 177 615 629

63. LitchfieldJTJr

WilcoxonF

1948 A simplified method of evaluating dose-effect experiments. Fed Proc 7 240

64. BenjaminiY

HochbergY

1995 Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing.

65. GuptaV

ParisiM

SturgillD

NuttallR

DoctoleroM

2006 Global analysis of X-chromosome dosage compensation. J Biol 5 3

66. EdgarR

DomrachevM

LashAE

2002 Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30 207 210

67. SmythGK

SpeedT

2003 Normalization of cDNA microarray data. Methods 31 265 273

68. BolstadBM

IrizarryRA

AstrandM

SpeedTP

2003 A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19 185 193

69. ReinerA

YekutieliD

BenjaminiY

2003 Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 19 368 375

70. KarolchikD

KuhnRM

BaertschR

BarberGP

ClawsonH

2008 The UCSC Genome Browser Database: 2008 update. Nucl Acids Res 36 D773 779

71. Huang daW

ShermanBT

LempickiRA

2009 Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4 44 57

72. DennisGJr

ShermanBT

HosackDA

YangJ

GaoW

2003 DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4 P3

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2010 Číslo 8
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#