title: Gene expression and genetic variation in response to endoplasmic reticulum stress in human cells.
abstract: The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in the condition called "ER stress," which induces the unfolded protein response (UPR), a complex cellular process that includes changes in expression of many genes. Failure to restore homeostasis in the ER is associated with human diseases. To identify the underlying changes in gene expression in response to ER stress, we induced ER stress in human B cells and then measured gene expression at ten time points. We followed up those results by studying cells from 60 unrelated people. We rediscovered genes that were known to play a role in the ER-stress response and uncovered several thousand genes that are not known to be involved. Two of these are VLDLR and INHBE, which showed significant increase in expression after ER stress in B cells and in primary fibroblasts. To study the links between UPR and disease susceptibility, we identified ER-stress-responsive genes that are associated with human diseases and assessed individual differences in the ER-stress response. Many of the UPR genes are associated with Mendelian disorders, such as Wolfram syndrome, and complex diseases, including amyotrophic lateral sclerosis and diabetes. Data from two independent samples showed extensive individual variability in ER-stress response. Additional analyses with monozygotic twins revealed significant correlations within twin pairs in their responses to ER stress, thus showing evidence for heritable variation among individuals. These results have implications for basic understanding of ER function and its role in disease susceptibility.
authors.affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Dombroski
authors.forename: Renuka R
authors.initials: RR
authors.lastname: Nayak
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Ewens
authors.forename: Wendy
authors.initials: W
authors.lastname: Ankener
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Cheung
authors.forename: Richard S
authors.initials: RS
authors.lastname: Spielman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D014644:Genetic Variation; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D011973:Receptors, LDL / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology
chemical_list: D011973:Receptors, LDL; C036053:VLDL receptor
references.citation: Nat Rev Genet. 2009 Mar;10(3):184-94
references.pmid: 19223927
references.citation: Mol Cell Biol. 2001 Feb;21(4):1239-48
references.pmid: 11158310
references.citation: J Clin Invest. 2002 Nov;110(10):1389-98
references.pmid: 12438434
references.citation: Nat Genet. 1998 Oct;20(2):143-8
references.pmid: 9771706
references.citation: Diabetes. 2009 Jun;58(6):1283-91
references.pmid: 19336676
references.citation: Nat Rev Drug Discov. 2008 Dec;7(12):1013-30
references.pmid: 19043451
references.citation: Nature. 1983 Nov 24-30;306(5941):387-9
references.pmid: 6417546
references.citation: Nat Genet. 2007 Oct;39(10):1202-7
references.pmid: 17873877
references.citation: Nephron. 2002 Jun;91(2):262-9
references.pmid: 12053063
references.citation: Biochem Biophys Res Commun. 1975 Jul 8;65(1):248-57
references.pmid: 167767
references.citation: J Biol Chem. 1998 Dec 11;273(50):33741-9
references.pmid: 9837962
references.citation: Nat Genet. 2003 Mar;33(3):422-5
references.pmid: 12567189
references.citation: Nat Rev Genet. 2009 Sep;10(9):595-604
references.pmid: 19636342
references.citation: Nature. 2008 Mar 27;452(7186):423-8
references.pmid: 18344981
references.citation: Cell. 1989 Nov 17;59(4):729-37
references.pmid: 2510935
references.citation: Cell. 2000 Apr 28;101(3):249-58
references.pmid: 10847680
references.citation: Nature. 2009 May 28;459(7246):587-91
references.pmid: 19349959
references.citation: J Biol Chem. 1997 Feb 14;272(7):4327-34
references.pmid: 9020152
references.citation: Cell. 1993 Jun 18;73(6):1197-206
references.pmid: 8513503
references.citation: Antioxid Redox Signal. 2009 Sep;11(9):2279-87
references.pmid: 19485711
references.citation: Mol Cell Biol. 2000 Sep;20(18):6755-67
references.pmid: 10958673
references.citation: Nature. 2004 Aug 12;430(7001):743-7
references.pmid: 15269782
references.citation: Hum Mol Genet. 2007 Feb 15;16(4):364-73
references.pmid: 17164263
references.citation: Hum Genomics. 2005 Jun;2(2):126-31
references.pmid: 16004727
references.citation: Dev Cell. 2003 Feb;4(2):265-71
references.pmid: 12586069
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15920-5
references.pmid: 12446838
references.citation: Annu Rev Biochem. 2005;74:739-89
references.pmid: 15952902
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Biochem Pharmacol. 1961 Feb;5:359-68
references.pmid: 13716779
references.citation: Cell. 2001 Dec 28;107(7):881-91
references.pmid: 11779464
references.citation: Arthritis Rheum. 2003 Jul;48(7):1858-72
references.pmid: 12847680
references.citation: Am J Hum Genet. 2007 Oct;81(4):673-83
references.pmid: 17846994
references.citation: Nature. 2005 Oct 27;437(7063):1365-9
references.pmid: 16251966
references.citation: Science. 2009 Mar 27;323(5922):1693-7
references.pmid: 19325107
references.citation: J Biol Chem. 2000 Sep 1;275(35):27013-20
references.pmid: 10856300
references.citation: Nat Genet. 2007 Oct;39(10):1208-16
references.pmid: 17873875
references.citation: Mol Biol Cell. 1999 Nov;10(11):3787-99
references.pmid: 10564271
references.citation: Nature. 1999 Jan 21;397(6716):271-4
references.pmid: 9930704
references.citation: Trends Mol Med. 2008 Jun;14(6):268-75
references.pmid: 18482868
references.citation: Am J Pathol. 1973 Jan;70(1):1-24
references.pmid: 4682838
references.citation: Nat Rev Immunol. 2008 Sep;8(9):663-74
references.pmid: 18670423