L Herteleer1,2,3, L Zwarts1,2,3, K Hens1,2,3,4, D Forero1,2,3,5,6,7, J Del-Favero5,6, P Callaerts8,9,10. 1. Laboratory of Behavioral and Developmental Genetics, VIB-KULeuven, Herestraat 49 bus 602, 3000, Leuven, Belgium. 2. KULeuven Department of Human Genetics, Leuven, Belgium. 3. VIB Center for the Biology of Disease, Leuven, Belgium. 4. Centre for Neural Circuits and Behavior, Oxford University, Oxford, UK. 5. Applied Molecular Genomics Group, VIB Department of Molecular Genetics, Leuven, Belgium. 6. University of Antwerp, Antwerp, Belgium. 7. Laboratory of Neuropsychiatric Genetics, School of Medicine, Antonio Narino University, Bogota, Colombia. 8. Laboratory of Behavioral and Developmental Genetics, VIB-KULeuven, Herestraat 49 bus 602, 3000, Leuven, Belgium. patrick.callaerts@cme.vib-kuleuven.be. 9. KULeuven Department of Human Genetics, Leuven, Belgium. patrick.callaerts@cme.vib-kuleuven.be. 10. VIB Center for the Biology of Disease, Leuven, Belgium. patrick.callaerts@cme.vib-kuleuven.be.
Abstract
RATIONALE: Lithium and valproate (VPA) are drugs used in the management of bipolar disorder. Even though they reportedly act on various pathways, the transcriptional targets relevant for disease mechanism and therapeutic effect remain unclear. Furthermore, multiple studies used lymphoblasts of bipolar patients as a cellular proxy, but it remains unclear whether peripheral cells provide a good readout for the effects of these drugs in the brain. OBJECTIVES: We used Drosophila culture cells and adult flies to analyze the transcriptional effects of lithium and VPA and define mechanistic pathways. METHODS: Transcriptional profiles were determined for Drosophila S2-cells and adult fly heads following lithium or VPA treatment. Gene ontology categories were identified using the DAVID functional annotation tool with a cut-off of p < 0.05. Significantly enriched GO terms were clustered using REVIGO and DAVID functional annotation clustering. Significance of overlap between transcript lists was determined with a Fisher's exact hypergeometric test. RESULTS: Treatment of cultured cells and adult flies with lithium and VPA induces transcriptional responses in genes with similar ontology, with as most prominent immune response, neuronal development, neuronal function, and metabolism. CONCLUSIONS: (i) Transcriptional effects of lithium and VPA in Drosophila S2 cells and heads show significant overlap. (ii) The overlap between transcriptional alterations in peripheral versus neuronal cells at the single gene level is negligible, but at the gene ontology and pathway level considerable overlap can be found. (iii) Lithium and VPA act on evolutionarily conserved pathways in Drosophila and mammalian models.
RATIONALE: Lithium and valproate (VPA) are drugs used in the management of bipolar disorder. Even though they reportedly act on various pathways, the transcriptional targets relevant for disease mechanism and therapeutic effect remain unclear. Furthermore, multiple studies used lymphoblasts of bipolarpatients as a cellular proxy, but it remains unclear whether peripheral cells provide a good readout for the effects of these drugs in the brain. OBJECTIVES: We used Drosophila culture cells and adult flies to analyze the transcriptional effects of lithium and VPA and define mechanistic pathways. METHODS: Transcriptional profiles were determined for Drosophila S2-cells and adult fly heads following lithium or VPA treatment. Gene ontology categories were identified using the DAVID functional annotation tool with a cut-off of p < 0.05. Significantly enriched GO terms were clustered using REVIGO and DAVID functional annotation clustering. Significance of overlap between transcript lists was determined with a Fisher's exact hypergeometric test. RESULTS: Treatment of cultured cells and adult flies with lithium and VPA induces transcriptional responses in genes with similar ontology, with as most prominent immune response, neuronal development, neuronal function, and metabolism. CONCLUSIONS: (i) Transcriptional effects of lithium and VPA in Drosophila S2 cells and heads show significant overlap. (ii) The overlap between transcriptional alterations in peripheral versus neuronal cells at the single gene level is negligible, but at the gene ontology and pathway level considerable overlap can be found. (iii) Lithium and VPA act on evolutionarily conserved pathways in Drosophila and mammalian models.
Authors: Elsa Boudadi; Hannah Stower; John A Halsall; Charlotte E Rutledge; Martin Leeb; Anton Wutz; Laura P O'Neill; Karl P Nightingale; Bryan M Turner Journal: Epigenetics Chromatin Date: 2013-05-01 Impact factor: 4.954
Authors: Priyanka Sinha; Simone L Cree; Allison L Miller; John F Pearson; Martin A Kennedy Journal: Pharmacogenomics J Date: 2021-03-01 Impact factor: 3.550