Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice
Abstract
:1. Introduction
2. Results
2.1. Spontaneous Apnea Counts are Greater in Mecp2-/y Mice Compared to WT Mice
2.2. VPA Treatment Reduces Apnea Counts in Mecp2-/y Mice
2.3. VPA Treatment Upregulates Gad1 mRNA Expression in the RVLM
2.4. VPA Treatment Enhances Histone Acetylation in the RVLM
2.5. VPA Treatment Induces Gad1 Promoter Demethylation in Mecp2-/Y Mice
2.6. VPA Treatment Reduces Tet1 mRNA Expression in Mecp2-/Y Mice
2.7. VPA Treatment Modifies Mbd1 Association with Gad1 Promoter in Mecp2-/Y Mice
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. VPA Treatment
4.3. Plethysmographic Assessment of Apnea Episodes
4.4. Isolation of Total RNA and Quantitative Reverse Transcription PCR Analysis
4.5. Quantitative Immunofluorescence Labelling
4.6. Sodium Bisulfite Mapping
4.7. Chromatin Immunoprecipitation Assay
4.8. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ANOVA | analysis of variance |
AP | area postrema |
cDNA | complementary DNA |
DNMT | DNA methyltransferase |
EGR1 | Early growth response protein 1 |
GABA | γ-aminobutyric acid |
GAPDH | glyceraldehyde 3-phosphate dehydrogenase |
HDAC | histone deacetylase |
MBD | Methyl-CpG binding domain protein |
MeCP2 | methyl-CpG-binding protein 2 |
NTS | nucleus tractus solitarius |
PCR | polymerase chain reaction |
RT-qPCR | quantitative reverse transcription PCR |
RTT | Rett syndrome |
RVLM | rostral ventrolateral medulla |
Sp5 | spinal trigeminal nucleus |
TDG | thymine DNA glycosylase |
TET | ten–eleven translocation |
TSS | transcriptional start site |
VPA | valproate |
XII | hypoglossal nucleus |
Appendix A
n | Breathing Frequency (Cycles/min) | Tidal Volume (mL) | Inspiratory Time (s) | Expiratory Time (s) | Peak Inspiratory Flow (mL/s) | Peak Expiratory Flow (mL/s) | |
WT—saline | 6 | 244.6 ± 2.4 | 0.061 ± 0.001 | 0.073 ± 0.002 | 0.156 ± 0.002 | 1.165 ± 0.005 | 1.031 ± 0.020 |
WT—VPA | 6 | 253.0 ± 4.7 | 0.051 ± 0.002 | 0.077 ± 0.002 | 0.167 ± 0.010 | 1.106 ± 0.024 | 1.036 ± 0.070 |
MeCP2-/y—saline | 6 | 235.6 ± 3.4 | 0.063 ± 0.004 | 0.089 ± 0.002 | 0.184 ± 0.010 | 1.126 ± 0.041 | 1.076 ± 0.044 |
MeCP2-/y—VPA | 6 | 239.0 ± 5.6 | 0.057 ± 0.001 | 0.085 ± 0.003 | 0.167 ± 0.004 | 1.062 ± 0.045 | 1.006 ± 0.028 |
Gene | Sequences (F; Forward, R; Reverse) | Genbank Number | |
---|---|---|---|
Gad1 | F | 5′-TTCTGGTACATTCCACAAAGCCTTC-3′ | NM_008077.5 |
R | 5′-CCATGGTTGTTCCTGACTCCATC-3′ | ||
Tet1 | F | 5′-TCAGCATGAAGTCTCAGTTGACTCC-3′ | NM_001253857.2 |
R | 5′-GAATTGATGCCTTATTCCCACCA-3′ | ||
Tet2 | F | 5′-GGTGCTACCCAGATTGCTCCA-3′ | NM_001040400.2 |
R | 5′-TGGTCTAAGCCTCCACTGTTAGCTC-3′ | ||
Tet3 | F | 5′-CTGTCCATCTCATGGAGCTTTC-3′ | NM_001347313.1 |
R | 5′-GCGTATGCACCTCCAATGTGTTA-3′ | ||
Dnmt1 | F | 5′-CTTCGGCAACATCCTGGACA-3′ | NM_001199431.1 |
R | 5′-ACTGGACAGCAGGCAGAGCTTA-3′ | ||
Dnmt3a | F | 5′-GCATACAGCTTGCTGCACTCTC-3′ | NM_153743.4 |
R | 5′-ACCTGCTGTACGCATTGACC-3′ | ||
Dnmt3b | F | 5′-TTGCTTTGGTACAAGGGCTGAA-3′ | NM_001003960.4 |
R | 5′-TCATCCCTGCTGACATCATCATC-3′ | ||
Tdg | F | 5′-TAGGAAACGTGCGTGTTCAG-3′ | NM_001358517.1 |
R | 5′-CTCATACTGCCAAACCAGCA-3′ | ||
Egr1 | F | 5′-TCAGTGGCCACCACCTTTG-3′ | NM_007913.5 |
R | 5′-AAAGGTCGCTGTCATGTCTGAA-3′ | ||
Gapdh | F | 5′-TGTGTCCGTCGTGGATCTGA-3′ | NM_008084.3 |
R | 5′-TTGCTGTTGAAGTCGCAGGAC-3′ |
No. of Mice Belonging to Each Group | No. of Mothers that Raised Mice Belonging to Each Group | Results of A Two-Factor ANOVA | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Genes | WT-saline | WT-VPA | Mecp2-/y-saline | Mecp2-/y-VPA | WT-saline | WT-VPA | Mecp2-/y-saline | Mecp2-/y-VPA | geno-type | treat-ment | inter-action |
Tet1 | 6 | 6 | 6 | 6 | 5 | 5 | 6 | 6 | n.s. | p < 0.01 | p < 0.05 |
Tet2 | 6 | 6 | 6 | 6 | 5 | 5 | 6 | 6 | n.s. | n.s. | n.s. |
Tet3 | 6 | 6 | 6 | 6 | 5 | 5 | 6 | 6 | p < 0.01 | n.s. | n.s. |
Dnmt1 | 8 | 8 | 8 | 8 | 7 | 7 | 7 | 7 | n.s. | n.s. | n.s. |
Dnmt3a | 11 | 12 | 10 | 12 | 10 | 10 | 10 | 11 | n.s. | n.s. | n.s. |
Dnmt3b | 6 | 6 | 6 | 6 | 5 | 5 | 6 | 6 | n.s. | n.s. | p < 0.01 |
Tdg | 12 | 11 | 10 | 10 | 10 | 10 | 10 | 10 | n.s. | n.s. | n.s. |
Egr1 | 12 | 11 | 12 | 12 | 10 | 10 | 10 | 11 | n.s. | n.s. | n.s. |
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Ishiyama, M.; Tamura, S.; Ito, H.; Takei, H.; Hoshi, M.; Asano, M.; Itoh, M.; Shirakawa, T. Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice. Int. J. Mol. Sci. 2019, 20, 5177. https://doi.org/10.3390/ijms20205177
Ishiyama M, Tamura S, Ito H, Takei H, Hoshi M, Asano M, Itoh M, Shirakawa T. Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice. International Journal of Molecular Sciences. 2019; 20(20):5177. https://doi.org/10.3390/ijms20205177
Chicago/Turabian StyleIshiyama, Misa, Satoko Tamura, Hisanori Ito, Hiroki Takei, Manami Hoshi, Masatake Asano, Masayuki Itoh, and Tetsuo Shirakawa. 2019. "Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice" International Journal of Molecular Sciences 20, no. 20: 5177. https://doi.org/10.3390/ijms20205177