Epistasis of Transcriptomes Reveals Synergism between Transcriptional Activators Hnf1α and Hnf4α

English version České info

The transcription of individual genes is determined by combinatorial interactions between DNA–binding transcription factors. The current challenge is to understand how such combinatorial interactions regulate broad genetic programs that underlie cellular functions and disease. The transcription factors Hnf1α and Hnf4α control pancreatic islet β-cell function and growth, and mutations in their genes cause closely related forms of diabetes. We have now exploited genetic epistasis to examine how Hnf1α and Hnf4α functionally interact in pancreatic islets. Expression profiling in islets from either Hnf1a^+/− or pancreas-specific Hnf4a mutant mice showed that the two transcription factors regulate a strikingly similar set of genes. We integrated expression and genomic binding studies and show that the shared transcriptional phenotype of these two mutant models is linked to common direct targets, rather than to known effects of Hnf1α on Hnf4a gene transcription. Epistasis analysis with transcriptomes of single- and double-mutant islets revealed that Hnf1α and Hnf4α regulate common targets synergistically. Hnf1α binding in Hnf4a-deficient islets was decreased in selected targets, but remained unaltered in others, thus suggesting that the mechanisms for synergistic regulation are gene-specific. These findings provide an in vivo strategy to study combinatorial gene regulation and reveal how Hnf1α and Hnf4α control a common islet-cell regulatory program that is defective in human monogenic diabetes.

Vyšlo v časopise: Epistasis of Transcriptomes Reveals Synergism between Transcriptional Activators Hnf1α and Hnf4α. PLoS Genet 6(5): e32767. doi:10.1371/journal.pgen.1000970
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000970

Souhrn

Zdroje

1. CareyM

SmaleST

2000 Transcriptional regulation in eukaryotes concepts, strategies, and techniques. Cold Spring Harbor, NY Cold Spring Harbor Laboratory Press

2. CostaRH

GraysonDR

DarnellJEJr

1989 Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol 9 1415 1425

3. DuW

ThanosD

ManiatisT

1993 Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. Cell 74 887 898

4. YuhCH

BolouriH

DavidsonEH

1998 Genomic cis-regulatory logic: experimental and computational analysis of a sea urchin gene. Science 279 1896 1902

5. HortonJD

ShahNA

WarringtonJA

AndersonNN

ParkSW

2003 Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A 100 12027 12032

6. OdomDT

ZizlspergerN

GordonDB

BellGW

RinaldiNJ

2004 Control of pancreas and liver gene expression by HNF transcription factors. Science 303 1378 1381

7. BlaisA

TsikitisM

Acosta-AlvearD

SharanR

KlugerY

2005 An initial blueprint for myogenic differentiation. Genes Dev 19 553 569

8. BojSF

ServitjaJM

MartinD

RiosM

TalianidisI

2009 The functional targets of the monogenic diabetes transcription factors HNF1{alpha} and HNF4{alpha} are highly conserved between mice and humans. Diabetes

9. LiXY

MacArthurS

BourgonR

NixD

PollardDA

2008 Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biol 6 e27 doi:10.1371/journal.pbio.0060027

10. LohYH

WuQ

ChewJL

VegaVB

ZhangW

2006 The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38 431 440

11. ServitjaJM

PignatelliM

MaestroMA

CardaldaC

BojSF

2009 Hnf1{alpha} (MODY3) controls tissue-specific transcriptional programs and exerts opposed effects on cell growth in pancreatic islets and liver. Mol Cell Biol

12. YangA

ZhuZ

KapranovP

McKeonF

ChurchGM

2006 Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Mol Cell 24 593 602

13. PhucLP

FriedmanJR

SchugJ

BrestelliJE

ParkerJB

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

14. YamagataK

FurutaH

OdaN

KaisakiPJ

MenzelS

1996 Mutations In the hepatocyte nuclear factor-4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384 458 460

15. YamagataK

OdaN

KaisakiPJ

MenzelS

FurutaH

1996 Mutations in the hepatocyte nuclear factor-1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384 455 458

16. StoffersDA

FerrerJ

ClarkeWL

HabenerJF

1997 Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 17 138 139

17. ServitjaJM

FerrerJ

2004 Transcriptional networks controlling pancreatic development and beta cell function. Diabetologia 47 597 613

18. MurphyR

EllardS

HattersleyAT

2008 Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 4 200 213

19. BojSF

ParrizasM

MaestroMA

FerrerJ

2001 A transcription factor regulatory circuit in differentiated pancreatic cells. Proceedings of the National Academy of Sciences of the United States of America 98 14481 14486

20. ThomasH

JaschkowitzK

BulmanM

FraylingTM

MitchellSM

2001 A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet 10 2089 2097

21. ShihDQ

ScreenanS

MunozKN

PhilipsonL

PontoglioM

2001 Loss of HNF-1 alpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes 50 2472 2480

22. EeckhouteJ

FormstecherP

LaineB

2004 Hepatocyte nuclear factor 4alpha enhances the hepatocyte nuclear factor 1alpha-mediated activation of transcription. Nucleic Acids Res 32 2586 2593

23. KtistakiE

TalianidisI

1997 Modulation of hepatic gene expression by hepatocyte nuclear factor 1. Science 277 109 112

24. RowleyCW

StalochLJ

DivineJK

McCaulSP

SimonTC

2006 Mechanisms of mutual functional interactions between HNF-4alpha and HNF-1alpha revealed by mutations that cause maturity onset diabetes of the young. Am J Physiol Gastrointest Liver Physiol 290 G466 G475

25. KyrmiziI

HatzisP

KatrakiliN

TroncheF

GonzalezFJ

2006 Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev 20 2293 2305

26. HuC

PerlmutterDH

1999 Regulation of alpha1-antitrypsin gene expression in human intestinal epithelial cell line caco-2 by HNF-1alpha and HNF-4. Am J Physiol 276 G1181 G1194

27. OzekiT

TakahashiY

KumeT

NakayamaK

YokoiT

2001 Co-operative regulation of the transcription of human dihydrodiol dehydrogenase (DD)4/aldo-keto reductase (AKR)1C4 gene by hepatocyte nuclear factor (HNF)-4alpha/gamma and HNF-1alpha. Biochem J 355 537 544

28. GuptaRK

VatamaniukMZ

LeeCS

FlaschenRC

FulmerJT

2005 The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 115 1006 1015

29. MiuraA

YamagataK

KakeiM

HatakeyamaH

TakahashiN

2006 Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem 281 5246 5257

30. PearsonER

BojSF

SteeleAM

BarrettT

StalsK

2007 Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 4 e118 doi:10.1371/journal.pmed.0040118

31. GuptaRK

GaoN

GorskiRK

WhiteP

HardyOT

2007 Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes Dev 21 756 769

32. ParvizF

MatulloC

GarrisonWD

SavatskiL

AdamsonJW

2003 Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34 292 296

33. DukesID

SreenanS

RoeMW

LevisettiM

ZhouYP

1998 Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice. J Biol Chem 273 24457 24464

34. LeeYH

SauerB

GonzalezFJ

1998 Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf- 1alpha knockout mouse. Mol Cell Biol 18 3059 3068

35. PontoglioM

SreenanS

RoeM

PughW

OstregaD

1998 Defective insulin secretion in hepatocyte nuclear factor 1 alpha-deficient mice. Journal of Clinical Investigation 101 2215 2222

36. ShihDQ

HeimesaatM

KuwajimaS

SteinR

WrightCV

2002 Profound defects in pancreatic beta -cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1alpha, and Hnf-3beta. Proc Natl Acad Sci U S A 99 3818 3823

37. van dePJ

KettelarijN

van BakelH

KockelkornTT

van LeenenD

2005 Mediator expression profiling epistasis reveals a signal transduction pathway with antagonistic submodules and highly specific downstream targets. Mol Cell 19 511 522

38. Van DriesscheN

DemsarJ

BoothEO

HillP

JuvanP

2005 Epistasis analysis with global transcriptional phenotypes. Nat Genet 37 471 477

39. CapaldiAP

KaplanT

LiuY

HabibN

RegevA

2008 Structure and function of a transcriptional network activated by the MAPK Hog1. Nat Genet 40 1300 1306

40. ParrizasM

MaestroMA

BojSF

PaniaguaA

CasamitjanaR

2001 Hepatic nuclear factor 1-alpha directs nucleosomal hyperacetylation to its tissue-specific transcriptional targets. Mol Cell Biol 21 3234 3243

41. BellGI

PolonskyKS

2001 Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 414 788 791

42. FerrerJ

2002 A genetic switch in pancreatic beta-cells - Implications for differentiation and haploinsufficiency. Diabetes 51 2355 2362

43. IharaA

YamagataK

NammoT

MiuraA

YuanM

2005 Functional characterization of the HNF4alpha isoform (HNF4alpha8) expressed in pancreatic beta-cells. Biochem Biophys Res Commun 329 984 990

44. HayhurstGP

LeeYH

LambertG

WardJM

GonzalezFJ

2001 Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21 1393 1403

45. HerreraPL

2000 Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127 2317 2322

46. LucoRF

MaestroMA

SadoniN

ZinkD

FerrerJ

2008 Targeted deficiency of the transcriptional activator Hnf1alpha alters subnuclear positioning of its genomic targets. PLoS Genet 4 e1000079 doi:10.1371/journal.pgen.1000079

47. Ho SuiSJ

FultonDL

ArenillasDJ

KwonAT

WassermanWW

2007 oPOSSUM: integrated tools for analysis of regulatory motif over-representation. Nucleic Acids Res 35 W245 W252

48. XieX

LuJ

KulbokasEJ

GolubTR

MoothaV

2005 Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434 338 345