DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons
Epigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activ...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/4/2034 |
| _version_ | 1797396040641413120 |
|---|---|
| author | Sarah Bachmann Jenice Linde Michael Bell Marc Spehr Hans Zempel Geraldine Zimmer-Bensch |
| author_facet | Sarah Bachmann Jenice Linde Michael Bell Marc Spehr Hans Zempel Geraldine Zimmer-Bensch |
| author_sort | Sarah Bachmann |
| collection | DOAJ |
| description | Epigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activity in excitatory and inhibitory cortical neurons in mice. Since DNA methylation signatures are responsive to neuronal activity, DNA methylation seems to contribute to the neuron’s capacity to adapt to and integrate changing activity patterns, being crucial for the plasticity and functionality of neuronal circuits. Since most studies addressing the role of DNA methylation in the regulation of synaptic function were conducted in mice or murine neurons, we here asked whether this functional implication applies to human neurons as well. To this end, we performed calcium imaging in human induced pluripotent stem cell (iPSC)-derived excitatory cortical neurons forming synaptic contacts and neuronal networks in vitro. Treatment with <i>DNMT1</i> siRNA that diminishs the expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) was conducted to investigate the functional relevance of DNMT1 as one of the main enzymes executing DNA methylations in the context of neuronal activity modulation. We observed a lowered proportion of actively firing neurons upon <i>DNMT1</i>-knockdown in these iPSC-derived excitatory neurons, pointing to a correlation of DNMT1-activity and synaptic transmission. Thus, our experiments suggest that DNMT1 decreases synaptic activity of human glutamatergic neurons and underline the relevance of epigenetic regulation of synaptic function also in human excitatory neurons. |
| first_indexed | 2024-03-09T00:45:33Z |
| format | Article |
| id | doaj.art-4dc2747d34164f3d8ce9a972bfeb31d0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:45:33Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4dc2747d34164f3d8ce9a972bfeb31d02023-12-11T17:33:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01224203410.3390/ijms22042034DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical NeuronsSarah Bachmann0Jenice Linde1Michael Bell2Marc Spehr3Hans Zempel4Geraldine Zimmer-Bensch5Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyFunctional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, 52074 Aachen, GermanyInstitute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyResearch Training Group 2416 MultiSenses-MultiScales, Institute for Biology II, RWTH Aachen University, 52074 Aachen, GermanyInstitute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyFunctional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, 52074 Aachen, GermanyEpigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activity in excitatory and inhibitory cortical neurons in mice. Since DNA methylation signatures are responsive to neuronal activity, DNA methylation seems to contribute to the neuron’s capacity to adapt to and integrate changing activity patterns, being crucial for the plasticity and functionality of neuronal circuits. Since most studies addressing the role of DNA methylation in the regulation of synaptic function were conducted in mice or murine neurons, we here asked whether this functional implication applies to human neurons as well. To this end, we performed calcium imaging in human induced pluripotent stem cell (iPSC)-derived excitatory cortical neurons forming synaptic contacts and neuronal networks in vitro. Treatment with <i>DNMT1</i> siRNA that diminishs the expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) was conducted to investigate the functional relevance of DNMT1 as one of the main enzymes executing DNA methylations in the context of neuronal activity modulation. We observed a lowered proportion of actively firing neurons upon <i>DNMT1</i>-knockdown in these iPSC-derived excitatory neurons, pointing to a correlation of DNMT1-activity and synaptic transmission. Thus, our experiments suggest that DNMT1 decreases synaptic activity of human glutamatergic neurons and underline the relevance of epigenetic regulation of synaptic function also in human excitatory neurons.https://www.mdpi.com/1422-0067/22/4/2034DNMT1human iPSClayer 2/3 cortical neuronssynaptic activityspontaneous activitycalcium imaging |
| spellingShingle | Sarah Bachmann Jenice Linde Michael Bell Marc Spehr Hans Zempel Geraldine Zimmer-Bensch DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons International Journal of Molecular Sciences DNMT1 human iPSC layer 2/3 cortical neurons synaptic activity spontaneous activity calcium imaging |
| title | DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons |
| title_full | DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons |
| title_fullStr | DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons |
| title_full_unstemmed | DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons |
| title_short | DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons |
| title_sort | dna methyltransferase 1 dnmt1 shapes neuronal activity of human ipsc derived glutamatergic cortical neurons |
| topic | DNMT1 human iPSC layer 2/3 cortical neurons synaptic activity spontaneous activity calcium imaging |
| url | https://www.mdpi.com/1422-0067/22/4/2034 |
| work_keys_str_mv | AT sarahbachmann dnamethyltransferase1dnmt1shapesneuronalactivityofhumanipscderivedglutamatergiccorticalneurons AT jenicelinde dnamethyltransferase1dnmt1shapesneuronalactivityofhumanipscderivedglutamatergiccorticalneurons AT michaelbell dnamethyltransferase1dnmt1shapesneuronalactivityofhumanipscderivedglutamatergiccorticalneurons AT marcspehr dnamethyltransferase1dnmt1shapesneuronalactivityofhumanipscderivedglutamatergiccorticalneurons AT hanszempel dnamethyltransferase1dnmt1shapesneuronalactivityofhumanipscderivedglutamatergiccorticalneurons AT geraldinezimmerbensch dnamethyltransferase1dnmt1shapesneuronalactivityofhumanipscderivedglutamatergiccorticalneurons |