#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Global Analysis of the Impact of Environmental Perturbation on -Regulation of Gene Expression


Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24h), and PGE2 (t = 24h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (ntotal = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene ±250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX–specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (∼1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here.


Vyšlo v časopise: Global Analysis of the Impact of Environmental Perturbation on -Regulation of Gene Expression. PLoS Genet 7(1): e32767. doi:10.1371/journal.pgen.1001279
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001279

Souhrn

Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24h), and PGE2 (t = 24h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (ntotal = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene ±250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX–specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (∼1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here.


Zdroje

1. DixonAL

LiangL

MoffattMF

ChenW

HeathS

2007 A genome-wide association study of global gene expression. Nat Genet 39 1202 1207

2. KwanT

BenovoyD

DiasC

GurdS

ProvencherC

2008 Genome-wide analysis of transcript isoform variation in humans. Nat Genet 40 225 231

3. StrangerBE

NicaAC

ForrestMS

DimasA

BirdCP

2007 Population genomics of human gene expression. Nat Genet 39 1217 1224

4. DimasAS

DeutschS

StrangerBE

MontgomerySB

BorelC

2009 Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325 1246 1250

5. EmilssonV

ThorleifssonG

ZhangB

LeonardsonAS

ZinkF

2008 Genetics of gene expression and its effect on disease. Nature 452 423 428

6. GoringHH

CurranJE

JohnsonMP

DyerTD

CharlesworthJ

2007 Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat Genet 39 1208 1216

7. GrundbergE

KwanT

GeB

LamKC

KokaV

2009 Population Genomics in a Disease Targeted Primary Cell Model. Genome Res

8. HeinzenEL

GeD

CroninKD

MaiaJM

ShiannaKV

2008 Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol 6 e1 doi:10.1371/journal.pbio.0060001

9. MyersAJ

GibbsJR

WebsterJA

RohrerK

ZhaoA

2007 A survey of genetic human cortical gene expression. Nat Genet 39 1494 1499

10. SchadtEE

MolonyC

ChudinE

HaoK

YangX

2008 Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6 e107 doi:10.1371/journal.pbio.0060107

11. LeeJH

ParkIH

GaoY

LiJB

LiZ

2009 A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells. PLoS Genet 5 e1000718 doi:10.1371/journal.pgen.1000718

12. SmirnovDA

MorleyM

ShinE

SpielmanRS

CheungVG

2009 Genetic analysis of radiation-induced changes in human gene expression. Nature 459 587 591

13. RomanoskiCE

LeeS

KimMJ

Ingram-DrakeL

PlaisierCL

Systems genetics analysis of gene-by-environment interactions in human cells. Am J Hum Genet 86 399 410

14. GrundbergE

BrandstromH

LamKC

GurdS

GeB

2008 Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells. Physiol Genomics 33 301 311

15. ChenD

JiX

HarrisMA

FengJQ

KarsentyG

1998 Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 142 295 305

16. LangdahlBL

KassemM

MollerMK

EriksenEF

1998 The effects of IGF-I and IGF-II on proliferation and differentiation of human osteoblasts and interactions with growth hormone. Eur J Clin Invest 28 176 183

17. KajiH

SugimotoT

KanataniM

FukaseM

KumegawaM

1996 Prostaglandin E2 stimulates osteoclast-like cell formation and bone-resorbing activity via osteoblasts: role of cAMP-dependent protein kinase. J Bone Miner Res 11 62 71

18. YaoZ

LiP

ZhangQ

SchwarzEM

KengP

2006 Tumor necrosis factor-alpha increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J Biol Chem 281 11846 11855

19. KimHJ

ZhaoH

KitauraH

BhattacharyyaS

BrewerJA

2006 Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 116 2152 2160

20. LocklinRM

KhoslaS

TurnerRT

RiggsBL

2003 Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone. J Cell Biochem 89 180 190

21. PandaDK

MiaoD

BolivarI

LiJ

HuoR

2004 Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 279 16754 16766

22. PastinenT

GeB

GurdS

GaudinT

DoreC

2005 Mapping common regulatory variants to human haplotypes. Hum Mol Genet 14 3963 3971

23. VerlaanDJ

GeB

GrundbergE

HobermanR

LamKC

2009 Targeted screening of cis-regulatory variation in human haplotypes. Genome Res 19 118 127

24. GeB

GurdS

GaudinT

DoreC

LepageP

2005 Survey of allelic expression using EST mining. Genome Res 15 1584 1591

25. PastinenT

SladekR

GurdS

SammakA

GeB

2004 A survey of genetic and epigenetic variation affecting human gene expression. Physiol Genomics 16 184 193

26. GeB

PokholokDK

KwanT

GrundbergE

MorcosL

2009 Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat Genet 41 1216 1222

27. LaitinenA

AltrajaA

KampeM

LindenM

VirtanenI

1997 Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med 156 951 958

28. IdaghdourY

CzikaW

ShiannaKV

LeeSH

VisscherPM

2010 Geographical genomics of human leukocyte gene expression variation in southern Morocco. Nat Genet 42 62 67

29. SmithEN

KruglyakL

2008 Gene-environment interaction in yeast gene expression. PLoS Biol 6 e83 doi:10.1371/journal.pbio.0060083

30. Cunninghame GrahamDS

GrahamRR

MankuH

WongAK

WhittakerJC

2008 Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nat Genet 40 83 89

31. DebloisG

GiguereV

2008 Nuclear receptor location analyses in mammalian genomes: from gene regulation to regulatory networks. Mol Endocrinol 22 1999 2011

32. ReddyTE

PauliF

SprouseRO

NeffNF

NewberryKM

2009 Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res 19 2163 2171

33. MidwoodK

SacreS

PiccininiAM

InglisJ

TrebaulA

2009 Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15 774 780

34. ZhaoY

1999 Tenascin is expressed in the mesenchyme of the embryonic lung and down-regulated by dexamethasone in early organogenesis. Biochem Biophys Res Commun 263 597 602

35. WangD

ChenH

MomaryKM

CavallariLH

JohnsonJA

2008 Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood 112 1013 1021

36. GentlemanRC

CareyVJ

BatesDM

BolstadB

DettlingM

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

37. 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

38. IrizarryRA

HobbsB

CollinF

Beazer-BarclayYD

AntonellisKJ

2003 Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4 249 264

39. BaldiP

LongAD

2001 A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics 17 509 519

40. StoreyJD

TibshiraniR

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

41. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575

42. LiY

AbecasisG

2006 Mach 1.0: Rapid Haplotype Reconstruction and Missing Genotype Inference. Am J Hum Genet S79 2290

43. LiY

WillerC

SannaS

AbecasisG

2009 Genotype imputation. Annu Rev Genomics Hum Genet 10 387 406

44. LiY

WillerC

DingJ

ScheetP

AbecasisG

2006 Rapid Markov Chain Haplotyping and Genotype Inference. Submitted

45. HaoK

ChudinE

McElweeJ

SchadtEE

2009 Accuracy of genome-wide imputation of untyped markers and impacts on statistical power for association studies. BMC Genet 10 27

46. BrowningSR

BrowningBL

2007 Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet 81 1084 1097

47. 2000 Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 343 1054 1063

48. HimesBE

HunninghakeGM

BaurleyJW

RafaelsNM

SleimanP

2009 Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 84 581 593

49. TantisiraKG

LakeS

SilvermanES

PalmerLJ

LazarusR

2004 Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet 13 1353 1359

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2011 Číslo 1
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#