SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients

Sierk Haenisch, Yi Zhao, Aparna Chhibber, Kitti Kaiboriboon, Lynn V. Do, Silke Vogelgesang, Nicholas Barbaro, Brian K. Alldredge, Daniel H. Lowenstein, Ingolf Cascorbi, Deanna L. Kroetz

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n. =. 8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p. =. 0.014), hsa-miR-212-3p: mean decrease of 76.9% (p. =. 0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.

Original languageEnglish
Pages (from-to)127-140
Number of pages14
JournalNeurobiology of Disease
Volume77
DOIs
StatePublished - May 1 2015

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Cell- and Tissue-Based Therapy
MicroRNAs
Epilepsy
SOXC Transcription Factors
Brain
Temporal Lobe Epilepsy
3' Untranslated Regions
Genes
RNA Interference
Reporter Genes
Neurons
Small Untranslated RNA
Gliosis
Partial Epilepsy
Neocortex
Neurogenesis
Nervous System Diseases
Computer Simulation
Transfection
Hippocampus

Keywords

  • Epilepsy
  • GABA
  • Glutamate
  • Hsa-miR-34c-5p
  • MicroRNA
  • MiR-132-3p
  • MiR-212-3p
  • Neurogenesis
  • Neuronal differentiation
  • SOX11
  • Temporal lobe

ASJC Scopus subject areas

  • Neurology

Cite this

SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients. / Haenisch, Sierk; Zhao, Yi; Chhibber, Aparna; Kaiboriboon, Kitti; Do, Lynn V.; Vogelgesang, Silke; Barbaro, Nicholas; Alldredge, Brian K.; Lowenstein, Daniel H.; Cascorbi, Ingolf; Kroetz, Deanna L.

In: Neurobiology of Disease, Vol. 77, 01.05.2015, p. 127-140.

Research output: Contribution to journalArticle

Haenisch, S, Zhao, Y, Chhibber, A, Kaiboriboon, K, Do, LV, Vogelgesang, S, Barbaro, N, Alldredge, BK, Lowenstein, DH, Cascorbi, I & Kroetz, DL 2015, 'SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients', Neurobiology of Disease, vol. 77, pp. 127-140. https://doi.org/10.1016/j.nbd.2015.02.025
Haenisch, Sierk ; Zhao, Yi ; Chhibber, Aparna ; Kaiboriboon, Kitti ; Do, Lynn V. ; Vogelgesang, Silke ; Barbaro, Nicholas ; Alldredge, Brian K. ; Lowenstein, Daniel H. ; Cascorbi, Ingolf ; Kroetz, Deanna L. / SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients. In: Neurobiology of Disease. 2015 ; Vol. 77. pp. 127-140.
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AU - Zhao, Yi

AU - Chhibber, Aparna

AU - Kaiboriboon, Kitti

AU - Do, Lynn V.

AU - Vogelgesang, Silke

AU - Barbaro, Nicholas

AU - Alldredge, Brian K.

AU - Lowenstein, Daniel H.

AU - Cascorbi, Ingolf

AU - Kroetz, Deanna L.

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N2 - MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n. =. 8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p. =. 0.014), hsa-miR-212-3p: mean decrease of 76.9% (p. =. 0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.

AB - MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n. =. 8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p. =. 0.014), hsa-miR-212-3p: mean decrease of 76.9% (p. =. 0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.

KW - Epilepsy

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KW - MiR-132-3p

KW - MiR-212-3p

KW - Neurogenesis

KW - Neuronal differentiation

KW - SOX11

KW - Temporal lobe

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