Neuronal and glial DNA methylation and gene expression changes in early epileptogenesis.
Animals
DNA Methylation
Disease Models, Animal
Epigenesis, Genetic
Epilepsy, Temporal Lobe
/ chemically induced
Galanin
/ genetics
Gene Expression Profiling
/ methods
Gene Expression Regulation
Gene Regulatory Networks
Genetic Predisposition to Disease
Histone Deacetylases
/ genetics
Kainic Acid
/ adverse effects
Male
Mice
Neuroglia
/ chemistry
Neurons
/ chemistry
Osteopontin
/ genetics
Receptors, Dopamine D1
/ genetics
Sequence Analysis, DNA
Sequence Analysis, RNA
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
18
07
2019
accepted:
28
11
2019
entrez:
31
12
2019
pubmed:
31
12
2019
medline:
28
3
2020
Statut:
epublish
Résumé
Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel therapeutic target. To our knowledge, this is the first study to investigate epilepsy-related DNAm, gene expression (GE) and their relationship, in neurons and glia. We used the intracortical kainic acid injection model to elicit status epilepticus. At 24 hours post injection, hippocampi from eight kainic acid- (KA) and eight saline-injected (SH) mice were extracted and shock frozen. Separation into neurons and glial nuclei was performed by flow cytometry. Changes in DNAm and gene expression were measured with reduced representation bisulfite sequencing (RRBS) and mRNA-sequencing (mRNAseq). Statistical analyses were performed in R with the edgeR package. We observed fulminant DNAm- and GE changes in both neurons and glia at 24 hours after initiation of status epilepticus. The vast majority of these changes were specific for either neurons or glia. At several epilepsy-related genes, like HDAC11, SPP1, GAL, DRD1 and SV2C, significant differential methylation and differential gene expression coincided. We found neuron- and glia-specific changes in DNAm and gene expression in early epileptogenesis. We detected single genetic loci in several epilepsy-related genes, where DNAm and GE changes coincide, worth further investigation. Further, our results may serve as an information source for neuronal and glial alterations in both DNAm and GE in early epileptogenesis.
Sections du résumé
BACKGROUND AND AIMS
Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel therapeutic target. To our knowledge, this is the first study to investigate epilepsy-related DNAm, gene expression (GE) and their relationship, in neurons and glia.
METHODS
We used the intracortical kainic acid injection model to elicit status epilepticus. At 24 hours post injection, hippocampi from eight kainic acid- (KA) and eight saline-injected (SH) mice were extracted and shock frozen. Separation into neurons and glial nuclei was performed by flow cytometry. Changes in DNAm and gene expression were measured with reduced representation bisulfite sequencing (RRBS) and mRNA-sequencing (mRNAseq). Statistical analyses were performed in R with the edgeR package.
RESULTS
We observed fulminant DNAm- and GE changes in both neurons and glia at 24 hours after initiation of status epilepticus. The vast majority of these changes were specific for either neurons or glia. At several epilepsy-related genes, like HDAC11, SPP1, GAL, DRD1 and SV2C, significant differential methylation and differential gene expression coincided.
CONCLUSION
We found neuron- and glia-specific changes in DNAm and gene expression in early epileptogenesis. We detected single genetic loci in several epilepsy-related genes, where DNAm and GE changes coincide, worth further investigation. Further, our results may serve as an information source for neuronal and glial alterations in both DNAm and GE in early epileptogenesis.
Identifiants
pubmed: 31887157
doi: 10.1371/journal.pone.0226575
pii: PONE-D-19-20265
pmc: PMC6936816
doi:
Substances chimiques
Drd1 protein, mouse
0
Receptors, Dopamine D1
0
Spp1 protein, mouse
0
Osteopontin
106441-73-0
Galanin
88813-36-9
Hdac11 protein, mouse
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Kainic Acid
SIV03811UC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0226575Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Nat Neurosci. 2019 Feb;22(2):307-316
pubmed: 30643296
J Cell Biochem. 2018 Aug;119(8):6337-6353
pubmed: 29377310
Brain. 1995 Feb;118 ( Pt 1):105-18
pubmed: 7894997
Brain Res. 1990 Dec 10;535(2):195-204
pubmed: 1705855
Cell Rep. 2017 Sep 19;20(12):2992-3003
pubmed: 28930691
Development. 1992 Sep;116(1):201-11
pubmed: 1483388
Mol Neurobiol. 2019 Mar;56(3):1825-1840
pubmed: 29934763
Sci Rep. 2017 Mar 09;7:43718
pubmed: 28276434
PLoS One. 2011 May 03;6(5):e19415
pubmed: 21559295
Glia. 2012 Aug;60(8):1203-14
pubmed: 22378467
Front Cell Neurosci. 2015 Feb 25;9:49
pubmed: 25762896
Science. 2015 Mar 6;347(6226):1138-42
pubmed: 25700174
Brain. 2015 May;138(Pt 5):1208-22
pubmed: 25765328
Neuroscience. 1997 Dec;81(3):707-20
pubmed: 9316023
Glia. 2006 Oct;54(5):358-68
pubmed: 16886201
Neuropeptides. 2018 Dec;72:23-29
pubmed: 30262417
Brain Res. 1989 Aug 28;495(2):387-95
pubmed: 2569920
F1000Res. 2017 Nov 28;6:2055
pubmed: 29333247
Nat Neurosci. 2011 Aug 28;14(10):1345-51
pubmed: 21874013
Glia. 2012 Aug;60(8):1192-202
pubmed: 22328245
J Neurosci. 1985 Apr;5(4):1016-22
pubmed: 3981241
Biochim Biophys Acta. 2005 Jun 10;1711(2):172-82
pubmed: 15955302
Genes (Basel). 2017 May 30;8(6):
pubmed: 28556790
Genome Res. 2011 May;21(5):688-96
pubmed: 21467265
Endocr Rev. 2001 Apr;22(2):153-83
pubmed: 11294822
Cell. 2016 Oct 20;167(3):587
pubmed: 27768878
Cell. 1998 Nov 13;95(4):521-30
pubmed: 9827804
Epilepsia. 2008 Oct;49(10):1675-85
pubmed: 18522644
Hum Mol Genet. 2015 Jun 1;24(11):3082-91
pubmed: 25691535
Cell. 2008 Nov 14;135(4):749-62
pubmed: 19013282
Epilepsia. 2010 May;51(5):883-90
pubmed: 20067507
Nat Rev Mol Cell Biol. 2001 May;2(5):327-38
pubmed: 11331907
Exp Neurol. 2013 Jun;244:4-10
pubmed: 21925173
Cell. 2016 Sep 22;167(1):233-247.e17
pubmed: 27662091
Eur J Neurosci. 2006 Mar;23(5):1269-82
pubmed: 16553789
Nat Rev Drug Discov. 2013 Oct;12(10):757-76
pubmed: 24052047
Oncotarget. 2016 Dec 27;7(52):87402-87416
pubmed: 27903967
Science. 2013 Aug 9;341(6146):1237905
pubmed: 23828890
Sci Rep. 2016 May 09;6:25668
pubmed: 27157830
Epilepsy Behav. 2009 Jan;14 Suppl 1:16-25
pubmed: 18835369
Genome Biol. 2012 Oct 03;13(10):R92
pubmed: 23034176
Nat Rev Drug Discov. 2010 Nov;9(11):883-97
pubmed: 21031003
Bioinformatics. 2017 Aug 1;33(15):2381-2383
pubmed: 28369316
Mol Biol Cell. 2015 Aug 1;26(15):2755-68
pubmed: 26063728
Stem Cells Int. 2018 Jul 8;2018:7834175
pubmed: 30123293
Prog Brain Res. 2006;158:223-41
pubmed: 17027699
Chem Rec. 2018 Dec;18(12):1717-1726
pubmed: 30066981
Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19802-7
pubmed: 24248345
BMC Neurosci. 2008 Apr 28;9:42
pubmed: 18442397
Neurology. 1998 Nov;51(5):1256-62
pubmed: 9818842
J Mol Neurosci. 2012 Feb;46(2):420-6
pubmed: 21826395
Epilepsia. 2016 Mar;57(3):376-85
pubmed: 26799155
J Biol Chem. 2006 Feb 3;281(5):2639-48
pubmed: 16314422
J Neurosci. 2012 May 2;32(18):6391-410
pubmed: 22553043
J Neurosci. 2008 Jan 2;28(1):264-78
pubmed: 18171944
Glia. 2012 Aug;60(8):1251-7
pubmed: 22378298
Nat Rev Neurosci. 2019 May;20(5):282-297
pubmed: 30792501
Exp Neurol. 2015 Nov;273:92-104
pubmed: 26238735
J Neurosci. 2007 Dec 12;27(50):13781-92
pubmed: 18077690
J Neurosci. 2009 Jan 28;29(4):883-97
pubmed: 19176798
Epilepsia. 2003 May;44(5):677-87
pubmed: 12752467
PLoS One. 2018 Dec 26;13(12):e0209648
pubmed: 30586455
Brain. 2007 Jul;130(Pt 7):1942-56
pubmed: 17533168
Front Cell Neurosci. 2015 May 07;9:175
pubmed: 25999819
Neurotherapeutics. 2014 Apr;11(2):231-41
pubmed: 24492975
Front Neuroanat. 2018 Oct 23;12:83
pubmed: 30405363
Glia. 2012 Aug;60(8):1191
pubmed: 22696194
Neuroscience. 2013 Sep 17;248:602-19
pubmed: 23811393
J Neurosci. 1990 Jan;10(1):267-82
pubmed: 1688934
Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):2012-2017
pubmed: 28167760
Science. 1996 Jan 26;271(5248):509-12
pubmed: 8560266
Lancet Neurol. 2011 Feb;10(2):173-86
pubmed: 21256455
Biochim Biophys Acta. 2008 Sep;1781(9):459-66
pubmed: 18485923
Sci Rep. 2017 Mar 27;7:45173
pubmed: 28345671
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Epigenetics Chromatin. 2018 Jul 25;11(1):41
pubmed: 30045751
Acta Neuropathol. 2013 Nov;126(5):741-56
pubmed: 24005891
Brain. 2015 Mar;138(Pt 3):616-31
pubmed: 25552301
Neuroscience. 2010 Feb 17;165(4):1301-11
pubmed: 19958814
Oncotarget. 2017 Jul 11;8(28):46286-46297
pubmed: 28611277
Neuropathol Appl Neurobiol. 2014 Feb;40(2):191-204
pubmed: 23617838
Epilepsia. 2013 Jul;54(7):1315-29
pubmed: 23692496
PLoS One. 2013 Oct 02;8(10):e76299
pubmed: 24098468
BMC Genomics. 2007 Sep 25;8:340
pubmed: 17894886
Glia. 2012 Aug;60(8):1234-43
pubmed: 22700220
Nat Immunol. 2009 Jan;10(1):92-100
pubmed: 19011628
Neuropharmacology. 2017 Jun;119:1-14
pubmed: 28373076
Science. 2009 Feb 20;323(5917):1074-7
pubmed: 19119186
Epilepsia. 2005 Apr;46(4):470-2
pubmed: 15816939
Sci Rep. 2017 Mar 09;7:43810
pubmed: 28276448
Science. 2018 Sep 28;361(6409):1336-1340
pubmed: 30262495
Nat Protoc. 2018 Apr;13(4):738-751
pubmed: 29565899
Epilepsia. 2005 Nov;46(11):1724-43
pubmed: 16302852
Glia. 2012 Aug;60(8):1227-33
pubmed: 22389222
Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):E2253-E2262
pubmed: 28246328
EMBO J. 2002 Apr 2;21(7):1514-23
pubmed: 11927536
Glia. 2012 Aug;60(8):1258-68
pubmed: 22331574
Nat Rev Genet. 2013 Mar;14(3):204-20
pubmed: 23400093
Glia. 2012 Aug;60(8):1215-26
pubmed: 22592998
J Neurosci. 2012 Feb 1;32(5):1577-88
pubmed: 22302800
Nucleic Acids Res. 2014 Jan;42(1):109-27
pubmed: 24057217
J Clin Invest. 2013 Aug;123(8):3552-63
pubmed: 23863710
Front Synaptic Neurosci. 2018 Nov 27;10:45
pubmed: 30542276
Cell Mol Life Sci. 2008 Jun;65(12):1864-71
pubmed: 18500639
Epilepsia. 2011 Apr;52(4):657-78
pubmed: 21426333
Sci Rep. 2016 Apr 07;6:23757
pubmed: 27053114
Epilepsia. 2004 Jun;45(6):695-714
pubmed: 15144438
J Neuropathol Exp Neurol. 2012 Sep;71(9):814-25
pubmed: 22878665
Biochim Biophys Acta Biomembr. 2017 Sep;1859(9 Pt B):1573-1582
pubmed: 28315304
Glia. 2014 Sep;62(9):1377-91
pubmed: 24807023
Am J Pathol. 2011 Nov;179(5):2519-32
pubmed: 21945804