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 medicínaČlánok vyšiel v časopise
PLOS Genetics
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