Reelin Promoter Hypermethylation in Schizophrenia

Reelin mRNA and protein levels are reduced by ≈50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 26; pp. 9341 - 9346
Main Authors Grayson, Dennis R., Jia, Xiaomei, Chen, Ying, Sharma, Rajiv P., Mitchell, Colin P., Guidotti, Alessandro, Costa, Erminio
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 28.06.2005
National Acad Sciences
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Abstract Reelin mRNA and protein levels are reduced by ≈50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and -139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.
AbstractList Reelin mRNA and protein levels are reduced by ≈50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and 139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status. DNA methyltransferase epigenetics gene regulation methylation psychiatric disorder
Reelin mRNA and protein levels are reduced by ≈50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and 139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.
Reelin mRNA and protein levels are reduced by approximately 50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and 139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.
Reelin mRNA and protein levels are reduced by {approx}50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and 139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status. [PUBLICATION ABSTRACT]
Reelin mRNA and protein levels are reduced by approximately 50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and 139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.Reelin mRNA and protein levels are reduced by approximately 50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and 139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.
Author Sharma, Rajiv P.
Jia, Xiaomei
Grayson, Dennis R.
Chen, Ying
Mitchell, Colin P.
Guidotti, Alessandro
Costa, Erminio
AuthorAffiliation Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, 1601 West Taylor Street, Chicago, IL 60612
AuthorAffiliation_xml – name: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, 1601 West Taylor Street, Chicago, IL 60612
Author_xml – sequence: 1
  givenname: Dennis R.
  surname: Grayson
  fullname: Grayson, Dennis R.
– sequence: 2
  givenname: Xiaomei
  surname: Jia
  fullname: Jia, Xiaomei
– sequence: 3
  givenname: Ying
  surname: Chen
  fullname: Chen, Ying
– sequence: 4
  givenname: Rajiv P.
  surname: Sharma
  fullname: Sharma, Rajiv P.
– sequence: 5
  givenname: Colin P.
  surname: Mitchell
  fullname: Mitchell, Colin P.
– sequence: 6
  givenname: Alessandro
  surname: Guidotti
  fullname: Guidotti, Alessandro
– sequence: 7
  givenname: Erminio
  surname: Costa
  fullname: Costa, Erminio
BackLink https://www.ncbi.nlm.nih.gov/pubmed/15961543$$D View this record in MEDLINE/PubMed
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Abbreviations: Dnmt, DNA methyl transferase; GAD, glutamic acid decarboxylase; NPS, nonpsychiatric subject(s); NT2, Ntera 2; RA, retinoic acid; SZP, schizophrenia patient(s).
Author contributions: D.R.G., A.G., and E.C. designed research; D.R.G., X.J., Y.C., R.P.S., and C.P.M. performed research; D.R.G. contributed new reagents/analytic tools; D.R.G., X.J., and Y.C. analyzed data; and D.R.G. wrote the paper.
Contributed by Erminio Costa, May 10, 2005
To whom correspondence should be addressed. E-mail: dgrayson@psych.uic.edu.
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Snippet Reelin mRNA and protein levels are reduced by ≈50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar...
Reelin mRNA and protein levels are reduced by approximately 50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia...
Reelin mRNA and protein levels are reduced by {approx}50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or...
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StartPage 9341
SubjectTerms Binding, Competitive
Biological Sciences
Brain
Cell Adhesion Molecules, Neuronal - genetics
Cell extracts
Cell lines
CpG Islands
Cytosine - chemistry
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA Methylation
Extracellular Matrix Proteins - genetics
Gene Expression Regulation
Genes, Reporter
Genomics
Humans
Kinetics
Mental disorders
Messenger RNA
Methylation
Models, Genetic
Nerve Tissue Proteins - genetics
Neurons
Oligonucleotides
Oligonucleotides - chemistry
Promoter regions
Promoter Regions, Genetic
Proteins
Ribonucleic acid
RNA
RNA, Messenger - metabolism
Schizophrenia
Schizophrenia - genetics
Sequence Analysis, DNA
Serine Endopeptidases - genetics
Sulfites - pharmacology
Time Factors
Transfection
Title Reelin Promoter Hypermethylation in Schizophrenia
URI https://www.jstor.org/stable/3375897
http://www.pnas.org/content/102/26/9341.abstract
https://www.ncbi.nlm.nih.gov/pubmed/15961543
https://www.proquest.com/docview/201415046
https://www.proquest.com/docview/17558676
https://www.proquest.com/docview/67990446
https://pubmed.ncbi.nlm.nih.gov/PMC1166626
Volume 102
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