Abstract
High levels of DNA methyltransferase 1 (DNMT1), hypermethylation, and downregulation of GAD 67 and reelin have been described in GABAergic interneurons of patients with schizophrenia (SZ) and bipolar (BP) disorders. However, overexpression of DNMT1 is lethal, making it difficult to assess the direct effect of high levels of DNMT1 on neuronal development in vivo. We therefore used Dnmt1 tet/tet mouse ES cells that overexpress DNMT1 as an in vitro model to investigate the impact of high levels of DNMT1 on neuronal differentiation. Although there is down-regulation of DNMT1 during early stages of differentiation in wild type and Dnmt1 tet/tet ES cell lines, neurons derived from Dnmt1 tet/tet cells showed abnormal dendritic arborization and branching. The Dnmt1 tet/tet neuronal cells also showed elevated levels of functional N-methyl d-aspartate receptor (NMDAR), a feature also reported in some neurological and neurodegenerative disorders. Considering the roles of reelin and GAD 67 in neuronal networking and excitatory/inhibitory balance, respectively, we studied methylation of these genes' promoters in Dnmt1 tet/tet ES cells and neurons. Both reelin and GAD 67 promoters were not hypermethylated in the Dnmt1 tet/tet ES cells and neurons, suggesting that overexpression of DNMT1 may not directly result in methylation-mediated repression of these two genes. Taken together, our results suggest that overexpression of DNMT1 in ES cells results in an epigenetic change prior to the onset of differentiation. This epigenetic change in turn results in abnormal neuronal differentiation and upregulation of functional NMDA receptor.
| Original language | English |
|---|---|
| Pages (from-to) | 9-17 |
| Number of pages | 9 |
| Journal | Differentiation |
| Volume | 82 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jul 2011 |
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Keywords
- DNA methylation
- Dnmt1
- Epigenetic
- Neuronal differentiation
- NMDA receptor
ASJC Scopus subject areas
- Developmental Biology
- Cell Biology
- Molecular Biology
- Cancer Research
Cite this
Mouse ES cells overexpressing DNMT1 produce abnormal neurons with upregulated NMDA/NR1 subunit. / D'Aiuto, Leonardo; Di Maio, Roberto; Mohan, K. Naga; Minervini, Crescenzio; Saporiti, Federica; Soreca, Isabella; Greenamyre, J. Timothy; Chaillet, J. Richard.
In: Differentiation, Vol. 82, No. 1, 07.2011, p. 9-17.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mouse ES cells overexpressing DNMT1 produce abnormal neurons with upregulated NMDA/NR1 subunit
AU - D'Aiuto, Leonardo
AU - Di Maio, Roberto
AU - Mohan, K. Naga
AU - Minervini, Crescenzio
AU - Saporiti, Federica
AU - Soreca, Isabella
AU - Greenamyre, J. Timothy
AU - Chaillet, J. Richard
PY - 2011/7
Y1 - 2011/7
N2 - High levels of DNA methyltransferase 1 (DNMT1), hypermethylation, and downregulation of GAD 67 and reelin have been described in GABAergic interneurons of patients with schizophrenia (SZ) and bipolar (BP) disorders. However, overexpression of DNMT1 is lethal, making it difficult to assess the direct effect of high levels of DNMT1 on neuronal development in vivo. We therefore used Dnmt1 tet/tet mouse ES cells that overexpress DNMT1 as an in vitro model to investigate the impact of high levels of DNMT1 on neuronal differentiation. Although there is down-regulation of DNMT1 during early stages of differentiation in wild type and Dnmt1 tet/tet ES cell lines, neurons derived from Dnmt1 tet/tet cells showed abnormal dendritic arborization and branching. The Dnmt1 tet/tet neuronal cells also showed elevated levels of functional N-methyl d-aspartate receptor (NMDAR), a feature also reported in some neurological and neurodegenerative disorders. Considering the roles of reelin and GAD 67 in neuronal networking and excitatory/inhibitory balance, respectively, we studied methylation of these genes' promoters in Dnmt1 tet/tet ES cells and neurons. Both reelin and GAD 67 promoters were not hypermethylated in the Dnmt1 tet/tet ES cells and neurons, suggesting that overexpression of DNMT1 may not directly result in methylation-mediated repression of these two genes. Taken together, our results suggest that overexpression of DNMT1 in ES cells results in an epigenetic change prior to the onset of differentiation. This epigenetic change in turn results in abnormal neuronal differentiation and upregulation of functional NMDA receptor.
AB - High levels of DNA methyltransferase 1 (DNMT1), hypermethylation, and downregulation of GAD 67 and reelin have been described in GABAergic interneurons of patients with schizophrenia (SZ) and bipolar (BP) disorders. However, overexpression of DNMT1 is lethal, making it difficult to assess the direct effect of high levels of DNMT1 on neuronal development in vivo. We therefore used Dnmt1 tet/tet mouse ES cells that overexpress DNMT1 as an in vitro model to investigate the impact of high levels of DNMT1 on neuronal differentiation. Although there is down-regulation of DNMT1 during early stages of differentiation in wild type and Dnmt1 tet/tet ES cell lines, neurons derived from Dnmt1 tet/tet cells showed abnormal dendritic arborization and branching. The Dnmt1 tet/tet neuronal cells also showed elevated levels of functional N-methyl d-aspartate receptor (NMDAR), a feature also reported in some neurological and neurodegenerative disorders. Considering the roles of reelin and GAD 67 in neuronal networking and excitatory/inhibitory balance, respectively, we studied methylation of these genes' promoters in Dnmt1 tet/tet ES cells and neurons. Both reelin and GAD 67 promoters were not hypermethylated in the Dnmt1 tet/tet ES cells and neurons, suggesting that overexpression of DNMT1 may not directly result in methylation-mediated repression of these two genes. Taken together, our results suggest that overexpression of DNMT1 in ES cells results in an epigenetic change prior to the onset of differentiation. This epigenetic change in turn results in abnormal neuronal differentiation and upregulation of functional NMDA receptor.
KW - DNA methylation
KW - Dnmt1
KW - Epigenetic
KW - Neuronal differentiation
KW - NMDA receptor
UR - http://www.scopus.com/inward/record.url?scp=79958769687&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79958769687&partnerID=8YFLogxK
U2 - 10.1016/j.diff.2011.03.003
DO - 10.1016/j.diff.2011.03.003
M3 - Article
C2 - 21492995
AN - SCOPUS:79958769687
VL - 82
SP - 9
EP - 17
JO - Differentiation
JF - Differentiation
SN - 0301-4681
IS - 1
ER -