title: The genetic architecture of the genome-wide transcriptional response to ER stress in the mouse.
abstract: Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. The cellular response to ER stress involves complex transcriptional and translational changes, important to the survival of the cell. ER stress is a primary cause and a modifier of many human diseases. A first step to understanding how the ER stress response impacts human disease is to determine how the transcriptional response to ER stress varies among individuals. The genetic diversity of the eight mouse Collaborative Cross (CC) founder strains allowed us to determine how genetic variation impacts the ER stress transcriptional response. We used tunicamycin, a drug commonly used to induce ER stress, to elicit an ER stress response in mouse embryonic fibroblasts (MEFs) derived from the CC founder strains and measured their transcriptional responses. We identified hundreds of genes that differed in response to ER stress across these genetically diverse strains. Strikingly, inflammatory response genes differed most between strains; major canonical ER stress response genes showed relatively invariant responses across strains. To uncover the genetic architecture underlying these strain differences in ER stress response, we measured the transcriptional response to ER stress in MEFs derived from a subset of F1 crosses between the CC founder strains. We found a unique layer of regulatory variation that is only detectable under ER stress conditions. Over 80% of the regulatory variation under ER stress derives from cis-regulatory differences. This is the first study to characterize the genetic variation in ER stress transcriptional response in the laboratory mouse. Our findings indicate that the ER stress transcriptional response is highly variable among strains and arises from genetic variation in individual downstream response genes, rather than major signaling transcription factors. These results have important implications for understanding how genetic variation impacts the ER stress response, an important component of many human diseases.
authors: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors: Clement Y
authors: CY
authors: Chow
authors: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors: Xu
authors: X
authors: Wang
authors: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors: David
authors: D
authors: Riccardi
authors: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors: Mariana F
authors: MF
authors: Wolfner
authors: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors: Andrew G
authors: AG
authors: Clark
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors
references: Heredity (Edinb). 2014 Aug;113(2):156-66
references: 24619182
references: J Biol Chem. 2001 Mar 23;276(12):9199-205
references: 11112790
references: J Biol Chem. 2010 Apr 30;285(18):13694-703
references: 20197277
references: Genome Res. 2004 Oct;14(10A):1880-7
references: 15466288
references: Am J Hum Genet. 2010 May 14;86(5):719-29
references: 20398888
references: PLoS One. 2012;7(10):e45078
references: 23110043
references: Bioinformatics. 2010 Jan 1;26(1):139-40
references: 19910308
references: Nat Genet. 2008 Mar;40(3):346-50
references: 18278046
references: Front Genet. 2013 Dec 02;4:256
references: 24348511
references: Int J Cell Biol. 2010;2010:830307
references: 20169136
references: PLoS One. 2008;3(12):e3839
references: 19052635
references: Annu Rev Cell Dev Biol. 2006;22:487-508
references: 16822172
references: J Biol Chem. 2007 Feb 9;282(6):3755-65
references: 17170114
references: Methods Enzymol. 2011;489:xvii
references: 21266220
references: Nucleic Acids Res. 2014 Feb;42(3):1757-71
references: 24170811
references: Bioinformatics. 2011 Feb 1;27(3):431-2
references: 21149340
references: Immunol Rev. 2012 Mar;246(1):193-204
references: 22435556
references: Bioinformatics. 2009 May 1;25(9):1105-11
references: 19289445
references: Mol Cell Biol. 2001 Feb;21(4):1239-48
references: 11158310
references: J Biol Chem. 1998 Dec 11;273(50):33741-9
references: 9837962
references: Nucleic Acids Res. 2009 Jan;37(1):1-13
references: 19033363
references: Nat Biotechnol. 2010 May;28(5):511-5
references: 20436464
references: J Clin Invest. 2008 Oct;118(10):3378-89
references: 18776938
references: Genome Res. 2010 Sep;20(9):1297-303
references: 20644199
references: Mol Cell Biol. 2011 Apr;31(8):1710-8
references: 21300786
references: Bioinformatics. 2014 Aug 1;30(15):2114-20
references: 24695404
references: Mamm Genome. 2012 Oct;23(9-10):713-8
references: 22892839
references: Hum Mol Genet. 2014 May 15;23(10):2629-38
references: 24368417
references: Hum Mol Genet. 2011 Mar 1;20(5):1008-15
references: 21159797
references: Proc Natl Acad Sci U S A. 2013 May 28;110(22):9013-8
references: 23667151
references: Genetics. 2012 Feb;190(2):437-47
references: 22345611
references: Genetics. 2014 Sep;198(1):59-73
references: 25236449
references: FEBS Lett. 2013 Apr 2;587(7):873-9
references: 23454656
references: J Clin Invest. 2002 Feb;109(4):525-32
references: 11854325
references: Nat Genet. 2004 Nov;36(11):1133-7
references: 15514660
references: Mamm Genome. 2008 Jun;19(6):382-9
references: 18716833
references: Mol Endocrinol. 2013 Apr;27(4):619-34
references: 23449887
references: Genome Res. 2012 Dec;22(12):2376-84
references: 22919075
references: Aging (Albany NY). 2010 Jun;2(6):369-74
references: 20606249
references: Genetics. 2013 Nov;195(3):1157-66
references: 24026101
references: Genome Res. 2011 Aug;21(8):1213-22
references: 21406540
references: Science. 2014 Mar 7;343(6175):1246949
references: 24604202
references: Cell. 2014 Mar 27;157(1):77-94
references: 24679528
references: Science. 2009 Sep 4;325(5945):1246-50
references: 19644074
references: Trends Biochem Sci. 2013 Sep;38(9):447-52
references: 23906563
references: Nucleic Acids Res. 2012 May;40(10):4288-97
references: 22287627
references: Science. 2000 Jan 28;287(5453):664-6
references: 10650002
references: Science. 1999 Jan 8;283(5399):217-20
references: 9880253
references: J Cell Biol. 2012 Jun 25;197(7):857-67
references: 22733998
references: Am J Physiol Cell Physiol. 2013 Jun 15;304(12):C1117-26
references: 23515532
references: PLoS Genet. 2011;7(2):e1002003
references: 21304890
references: J Biol Chem. 2009 Mar 20;284(12):7446-54
references: 19150982
references: Fly (Austin). 2012 Apr-Jun;6(2):80-92
references: 22728672
references: Bioinformatics. 2007 Nov 1;23(21):2881-7
references: 17881408
references: Mol Cell Biol. 2000 Sep;20(18):6755-67
references: 10958673
references: J Biol Chem. 2003 May 2;278(18):15558-64
references: 12601012
references: PLoS Biol. 2006 Nov;4(11):e374
references: 17090218
references: Nature. 2011 Sep 15;477(7364):289-94
references: 21921910
references: Genome Res. 2010 Jun;20(6):816-25
references: 20354124
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Mol Cell. 2001 Jun;7(6):1153-63
references: 11430819
references: Nature. 2011 Sep 15;477(7364):326-9
references: 21921916
references: Genetics. 2010 Dec;186(4):1355-65
references: 20876561
references: Nucleic Acids Res. 2005;33(10):3154-64
references: 15933209
references: IUBMB Life. 2013 May;65(5):373-81
references: 23554021
references: ILAR J. 2011;52(1):24-31
references: 21411855
references: Nucleic Acids Res. 1999 Mar 15;27(6):1437-43
references: 10037803
references: J Biochem. 2004 Sep;136(3):343-50
references: 15598891