title: Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon.
abstract: Schizophrenia (SZ) and autism spectrum disorders (ASD) are highly heritable neuropsychiatric disorders, although environmental factors, such as maternal immune activation (MIA), play a role as well. Cytokines mediate the effects of MIA on neurogenesis and behavior in animal models. However, MIA stimulators can also induce a febrile reaction, which could have independent effects on neurogenesis through heat shock (HS)-regulated cellular stress pathways. However, this has not been well-studied. To help understand the role of fever in MIA, we used a recently described model of human brain development in which induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional neuronal aggregates that resemble a first trimester telencephalon. RNA-seq was carried out on aggregates that were heat shocked at 39°C for 24 hours, along with their control partners maintained at 37°C. 186 genes showed significant differences in expression following HS (p<0.05), including known HS-inducible genes, as expected, as well as those coding for NGFR and a number of SZ and ASD candidates, including SMARCA2, DPP10, ARNT2, AHI1 and ZNF804A. The degree to which the expression of these genes decrease or increase during HS is similar to that found in copy loss and copy gain copy number variants (CNVs), although the effects of HS are likely to be transient. The dramatic effect on the expression of some SZ and ASD genes places HS, and perhaps other cellular stressors, into a common conceptual framework with disease-causing genetic variants. The findings also suggest that some candidate genes that are assumed to have a relatively limited impact on SZ and ASD pathogenesis based on a small number of positive genetic findings, such as SMARCA2 and ARNT2, may in fact have a much more substantial role in these disorders - as targets of common environmental stressors.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Dejian
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hrabovsky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Erika
authors.initials: E
authors.lastname: Pedrosa
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America; Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Lachman
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006358:Hot Temperature; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics*; D012867:Skin / Q000166:cytology; D013687:Telencephalon / Q000378:metabolism*
references.citation: PLoS One. 2011 Jan 18;6(1):e15886
references.pmid: 21267465
references.citation: Wiley Interdiscip Rev RNA. 2012 Nov-Dec;3(6):779-96
references.pmid: 22976942
references.citation: Dis Model Mech. 2012 Jan;5(1):26-32
references.pmid: 21954066
references.citation: Pediatrics. 2012 Dec;130(6):e1447-54
references.pmid: 23147969
references.citation: Mol Psychiatry. 2002;7 Suppl 2:S26-8
references.pmid: 12142940
references.citation: Hum Mol Genet. 2010 Jul 15;19(14):2841-57
references.pmid: 20457675
references.citation: Nature. 2012 Apr 04;485(7397):242-5
references.pmid: 22495311
references.citation: Mol Psychiatry. 2014 Feb;19(2):243-52
references.pmid: 24042478
references.citation: Nature. 2009 Aug 6;460(7256):744-7
references.pmid: 19571808
references.citation: J Neuroinflammation. 2012 Dec 11;9:265
references.pmid: 23231720
references.citation: Pediatrics. 2007 Dec;120(6):e1386-92
references.pmid: 18055656
references.citation: J Neuroimmunol. 2009 Feb 15;207(1-2):111-6
references.pmid: 19157572
references.citation: Toxicol Lett. 2011 Oct 10;206(2):152-7
references.pmid: 21771643
references.citation: Brain Behav Immun. 2012 Nov;26(8):1288-99
references.pmid: 22960545
references.citation: Brain Res Rev. 2009 Mar;59(2):388-92
references.pmid: 19059284
references.citation: Neurosci Biobehav Rev. 2009 Jul;33(7):1061-79
references.pmid: 19442688
references.citation: PLoS One. 2010 Aug 18;5(8):e12254
references.pmid: 20805890
references.citation: J Neurochem. 2013 Mar;124(6):880-93
references.pmid: 23121022
references.citation: J Affect Disord. 2010 Oct;126(1-2):312-6
references.pmid: 20451256
references.citation: PLoS One. 2012;7(1):e29754
references.pmid: 22238649
references.citation: Neuroscience. 2011 Sep 29;192:37-53
references.pmid: 21763404
references.citation: Nature. 2009 May 28;459(7246):569-73
references.pmid: 19404257
references.citation: Am J Psychiatry. 2011 Apr;168(4):408-17
references.pmid: 21324950
references.citation: Am J Psychiatry. 1995 May;152(5):738-48
references.pmid: 7726314
references.citation: Autism Res. 2009 Jun;2(3):157-77
references.pmid: 19598235
references.citation: Int J Hyperthermia. 2011;27(7):737-8
references.pmid: 21967199
references.citation: Bioinformatics. 2010 Feb 15;26(4):493-500
references.pmid: 20022975
references.citation: Clin Dysmorphol. 2011 Jan;20(1):38-41
references.pmid: 20802310
references.citation: Am J Med Genet. 1992 Jan 1;42(1):141-2
references.pmid: 1308357
references.citation: Int J Biol Macromol. 2013 Sep;60:196-205
references.pmid: 23748003
references.citation: Gene. 2013 Aug 1;525(1):107-15
references.pmid: 23644028
references.citation: Gene. 2013 Jun 15;522(2):184-91
references.pmid: 23542779
references.citation: PLoS One. 2013 Jul 30;8(7):e69115
references.pmid: 23935933
references.citation: Neurosignals. 2010;18(2):113-28
references.pmid: 20924155
references.citation: Neuroendocrinology. 2012;95(1):47-55
references.pmid: 22042385
references.citation: Neurosci Lett. 2009 May 29;456(1):39-43
references.pmid: 19429130
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1563-71
references.pmid: 18753265
references.citation: Biol Psychiatry. 2011 Jan 1;69(1):90-6
references.pmid: 20950796
references.citation: Horm Behav. 2013 Nov;64(5):833-9
references.pmid: 24100195
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2013 Dec;162B(8):847-54
references.pmid: 24115684
references.citation: Neuroscience. 2013 Nov 12;252:320-5
references.pmid: 23994594
references.citation: J Neurosci. 2010 Sep 29;30(39):13089-94
references.pmid: 20881126
references.citation: Schizophr Bull. 2009 May;35(3):528-48
references.pmid: 19223657
references.citation: Neurosci Biobehav Rev. 2014 Jan;38:17-37
references.pmid: 24216122
references.citation: Mol Psychiatry. 2013 Feb;18(2):226-35
references.pmid: 22105621
references.citation: Physiol Behav. 2010 Jun 1;100(3):255-63
references.pmid: 20045424
references.citation: Psychiatry Clin Neurosci. 2007 Feb;61(1):3-19
references.pmid: 17239033
references.citation: Mol Cell Endocrinol. 2007 Sep 15;275(1-2):2-12
references.pmid: 17628337
references.citation: PLoS One. 2008 Jul 09;3(7):e2595
references.pmid: 18612411
references.citation: Transl Psychiatry. 2012 Apr 03;2:e98
references.pmid: 22832908
references.citation: Am J Med Genet A. 2007 Nov 15;143A(22):2642-50
references.pmid: 17937445
references.citation: Cell Physiol Biochem. 2007;20(6):687-702
references.pmid: 17982252
references.citation: Neuroscience. 2013 Jun 3;239:157-72
references.pmid: 23069755
references.citation: J Neuroinflammation. 2012 Apr 30;9:83
references.pmid: 22546005
references.citation: Nat Genet. 2011 Aug 07;43(9):864-8
references.pmid: 21822266
references.citation: BMC Psychiatry. 2008 Aug 21;8:71
references.pmid: 18717990
references.citation: Schizophr Bull. 2014 Mar;40(2):351-61
references.pmid: 23328159
references.citation: Mol Psychiatry. 2014 May;19(5):568-72
references.pmid: 23689535
references.citation: JIMD Rep. 2014;13:91-9
references.pmid: 24190795
references.citation: Hum Mol Genet. 2012 Aug 1;21(15):3513-23
references.pmid: 22543975
references.citation: J Neurochem. 2008 Dec;107(5):1284-93
references.pmid: 18793330
references.citation: Nat Genet. 2011 Sep 18;43(10):969-76
references.pmid: 21926974
references.citation: Endocrinology. 2013 Sep;154(9):3261-72
references.pmid: 23633533
references.citation: Cell. 2012 Apr 27;149(3):525-37
references.pmid: 22521361
references.citation: Science. 2008 Apr 25;320(5875):539-43
references.pmid: 18369103
references.citation: Biochem Biophys Res Commun. 2006 Mar 24;341(4):1072-7
references.pmid: 16460681
references.citation: Brain Behav Immun. 2011 May;25(4):604-15
references.pmid: 21195166
references.citation: Transl Neurosci. 2012 Dec 1;3(4):320-327
references.pmid: 23956839
references.citation: J Psychiatr Res. 2012 Nov;46(11):1464-74
references.pmid: 22954356
references.citation: Biochim Biophys Acta. 2012 Jun;1822(6):831-42
references.pmid: 22326556
references.citation: Hum Genet. 2009 Jul;126(1):3-12
references.pmid: 19521722
references.citation: Curr Opin Otolaryngol Head Neck Surg. 2012 Dec;20(6):502-6
references.pmid: 23000736
references.citation: Nature. 2013 Sep 19;501(7467):373-9
references.pmid: 23995685
references.citation: Mol Psychiatry. 2012 Sep;17(9):887-905
references.pmid: 22584867
references.citation: J Alzheimers Dis. 2014;38(2):425-35
references.pmid: 23985416
references.citation: Neuroscience. 2012 Jun 1;211:13-27
references.pmid: 22465440
references.citation: Front Genet. 2013 Sep 20;4:181
references.pmid: 24065983
references.citation: Biol Psychiatry. 2014 Feb 15;75(4):262-8
references.pmid: 24199663
references.citation: Am J Hum Genet. 2008 Feb;82(2):477-88
references.pmid: 18252227
references.citation: Neuroscience. 2013 Oct 10;250:31-48
references.pmid: 23827308
references.citation: Biol Psychiatry. 2014 Feb 15;75(4):332-41
references.pmid: 24011823
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20935-40
references.pmid: 19104056
references.citation: Mol Psychiatry. 2010 Aug;15(8):778, 798-809
references.pmid: 20479754
references.citation: Science. 2000 Dec 15;290(5499):2155-9
references.pmid: 11118151
references.citation: Transl Psychiatry. 2012 Oct 16;2:e170
references.pmid: 23047241
references.citation: Front Genet. 2013 Nov 05;4:222
references.pmid: 24204377
references.citation: Nature. 2012 Sep 6;489(7414):57-74
references.pmid: 22955616
references.citation: J Clin Invest. 2013 Nov;123(11):4557-63
references.pmid: 24177465
references.citation: Genome Biol. 2010;11(10):R106
references.pmid: 20979621
references.citation: J Leukoc Biol. 2013 Dec;94(6):1167-84
references.pmid: 23990626
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 16;109 Suppl 2:17180-5
references.pmid: 23045648
references.citation: Am J Med Genet A. 2013 Jun;161A(6):1221-37
references.pmid: 23637025
references.citation: J Hum Genet. 2007;52(10):794-803
references.pmid: 17805476
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10164-9
references.pmid: 17553960
references.citation: Ann N Y Acad Sci. 2012 Jul;1261:55-63
references.pmid: 22823394
references.citation: J Biol Chem. 2005 May 13;280(19):18853-61
references.pmid: 15671030
references.citation: Br J Psychiatry. 2001 Nov;179:397-402
references.pmid: 11689394
references.citation: Endocrinology. 2012 Aug;153(8):3828-38
references.pmid: 22707478
references.citation: Mol Psychiatry. 2003 Jul;8(7):654-63
references.pmid: 12874601
references.citation: Genome Res. 2012 Sep;22(9):1760-74
references.pmid: 22955987
references.citation: Cancer Lett. 2013 Jul 10;335(1):52-7
references.pmid: 23395971
references.citation: Am J Physiol Cell Physiol. 2013 Jul 15;305(2):C197-206
references.pmid: 23703525
references.citation: Psychiatr Clin North Am. 2010 Mar;33(1):35-66
references.pmid: 20159339
references.citation: Biotech Histochem. 2012 Nov;87(8):506-11
references.pmid: 22853041
references.citation: Lancet. 1992 May 9;339(8802):1138-9
references.pmid: 1349369
references.citation: Am J Med Genet. 1992 Sep 15;44(2):261-8
references.pmid: 1360769
references.citation: Biol Psychiatry. 2013 May 15;73(10):951-66
references.pmid: 23414821
references.citation: Neurosci Res. 2009 Feb;63(2):122-8
references.pmid: 19059440
references.citation: Nature. 2009 Aug 6;460(7256):753-7
references.pmid: 19571809
references.citation: Arch Gen Psychiatry. 2004 Aug;61(8):774-80
references.pmid: 15289276
references.citation: Front Neuroendocrinol. 2009 Jan;30(1):30-45
references.pmid: 19017533
references.citation: Am J Psychiatry. 2014 Jan;171(1):62-71
references.pmid: 24170294
references.citation: Endocrinology. 2009 Apr;150(4):1850-60
references.pmid: 19022895
references.citation: Neuropharmacology. 2011 Jun;60(7-8):1232-42
references.pmid: 21184762
references.citation: Biol Psychiatry. 2014 Feb 15;75(4):276-83
references.pmid: 24199664
references.citation: Biol Psychiatry. 2004 Dec 15;56(12):943-50
references.pmid: 15601604
references.citation: Brain Res. 2008 Jul 24;1221:14-23
references.pmid: 18561899
references.citation: Biol Psychiatry. 2012 Nov 1;72(9):758-65
references.pmid: 22763186
references.citation: Genome Biol. 2013 Apr 25;14(4):R36
references.pmid: 23618408
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20049-54
references.pmid: 18056810
references.citation: Nat Genet. 2008 Sep;40(9):1053-5
references.pmid: 18677311
references.citation: J Autism Dev Disord. 2013 Jan;43(1):25-33
references.pmid: 22562209
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12770-5
references.pmid: 22761314
references.citation: Mol Psychiatry. 2010 Jan;15(1):29-37
references.pmid: 19844207
references.citation: Am J Hum Genet. 2008 Oct;83(4):504-10
references.pmid: 18940311
references.citation: PLoS One. 2011 Feb 10;6(2):e16638
references.pmid: 21347362
references.citation: Cleft Palate J. 1978 Jan;15(1):56-62
references.pmid: 272242
references.citation: Schizophr Bull. 2009 May;35(3):631-7
references.pmid: 18832344
references.citation: J Nerv Ment Dis. 1994 Aug;182(8):476-8
references.pmid: 8040660
references.citation: Biol Pharm Bull. 2013;36(10):1556-61
references.pmid: 23842035
references.citation: J Biol Regul Homeost Agents. 2012 Jul-Sep;26(3):347-56
references.pmid: 23034254
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10584-9
references.pmid: 20489179
references.citation: Hum Mol Genet. 2009 Jul 1;18(13):2483-94
references.pmid: 19363039
references.citation: Mol Psychiatry. 1998 Jul;3(4):346-9
references.pmid: 9702745
references.citation: Cell Death Dis. 2011 Apr 07;2:e141
references.pmid: 21472004
references.citation: Mol Biol Cell. 2014 Jan;25(1):169-83
references.pmid: 24173718
references.citation: Biochem Biophys Res Commun. 2005 Nov 4;336(4):1136-43
references.pmid: 16168956
references.citation: PLoS Genet. 2009 Feb;5(2):e1000373
references.pmid: 19197363
references.citation: Neuron Glia Biol. 2004 Aug;1(3):283-9
references.pmid: 18185853
references.citation: Mol Psychiatry. 2011 Jan;16(1):59-66
references.pmid: 20048749
references.citation: Adv Pharmacol. 2012;64:1-25
references.pmid: 22840743
references.citation: J Physiol Paris. 2013 Dec;107(6):434-40
references.pmid: 23792022
references.citation: Neurobiol Dis. 2008 Jun;30(3):303-311
references.pmid: 18378158
references.citation: Neuropediatrics. 2009 Jun;40(3):137-40
references.pmid: 20020400
references.citation: Hum Mol Genet. 2013 Dec 15;22(24):5001-14
references.pmid: 23904455