TY - JOUR
T1 - DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures
AU - de Nijs, Laurence
AU - Choe, Kyonghwan
AU - Steinbusch, Hellen
AU - Schijns, Olaf E. M. G.
AU - Dings, Jim
AU - van den Hove, Daniel L. A.
AU - Rutten, Bart P. F.
AU - Hoogland, Govert
N1 - Funding Information:
This research is supported by a grant from the Canadian Institute for Health Research (CIHR): 6210100362. Bioinformatics analyses were supported in part by the Canadian Centre for Computational Genomics (C3G), part of the Genome Technology Platform (GTP), funded by Genome Canada through Genome Quebec and Ontario Genomics (ALT and MB).
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/8/19
Y1 - 2019/8/19
N2 - Background Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS. Results We found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls. Conclusion Together, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted.
AB - Background Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS. Results We found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls. Conclusion Together, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted.
KW - Febrile seizures
KW - Temporal lobe epilepsy
KW - Epigenetics
KW - DNA methylation
KW - DNA methyltransferases
KW - HIPPOCAMPAL SCLEROSIS
KW - METHYLATION PATTERNS
KW - STATUS EPILEPTICUS
KW - DNMT3A
KW - MEMORY
KW - PROLIFERATION
KW - GENES
KW - BRAIN
UR - https://springernature.figshare.com/articles/dataset/Additional_file_4_of_DNA_methyltransferase_isoforms_expression_in_the_temporal_lobe_of_epilepsy_patients_with_a_history_of_febrile_seizures/9691961/1
UR - https://springernature.figshare.com/articles/dataset/Additional_file_5_of_DNA_methyltransferase_isoforms_expression_in_the_temporal_lobe_of_epilepsy_patients_with_a_history_of_febrile_seizures/9691967
UR - https://springernature.figshare.com/articles/dataset/Additional_file_6_of_DNA_methyltransferase_isoforms_expression_in_the_temporal_lobe_of_epilepsy_patients_with_a_history_of_febrile_seizures/9691973/1
U2 - 10.1186/s13148-019-0721-2
DO - 10.1186/s13148-019-0721-2
M3 - Article
C2 - 31426844
SN - 1868-7075
VL - 11
JO - Clinical epigenetics
JF - Clinical epigenetics
IS - 1
M1 - 118
ER -