BIOINFORMATIC INTERPRETATION OF TRACKING GENES OF MIRNA-LET 7B AND MIRNA-LET 7C IN DEPRESSION
Main Article Content
Keywords
Depression, miR-let-7b and miR-let-7c, CAMKK2 pathway and CREB
Abstract
Depression, a psychiatric disorder, has a profound impact on both physical and mental health. Despite its extensive prevalence, the complexity of its underlying causes, remains largely elusive. Growing interest has focused on microRNAs , endogenous short-stranded non-coding RNAs that inhibit, gene translation and are abundant in brain tissues. This study, conducted as portion of a clinical trial involving patients with depression, examined the plasma levels of miRNA-let-7b and miRNA-let-7c, which were observed to be down-regulated, in depression but showed improvement following treatment.The study aimed, to identify molecular genes associated with depression to uncover potential pathological mechanisms through bioinformatics. Using the miRabel database, we tracked genes and pathways affected by miRNA let-7b and let-7c in the context of depression. Differentially expressed genes and pathways were identified, with 37 tracking genes implicated in long-term depression. Through these, 11 genes had the highest potential impact: MAPK3, PLA2G4F, PLA2G4B, PLA2G4C, GNAZ, CACNA1A, GNA12, GRID2, ITPR3, ITPR1, and GUCY1A3.
These 11 genes affected various pathways, including the CAMKK2 pathway, CREB1 phosphorylation via NMDA receptor-mediated RAS signaling, and the regulation of neuron apoptotic processes. These pathways, are involved in neural circuits activated by stress and environmental factors, leading to intracellular signal transduction cascades that contributes to neural plasticity, in addition to cell persistence or demise. Disparity in neuronal adaptably, can lead to depression. In summary, signal transduction cascades and neuronal adaptability are crucial during the pathophysiology of depression, and these pathways are tracked by miR-let-7b and miR-let-7c.
References
2. Otte C., Gold S. M., Penninx B. W., et al. Major depressive disorder. Nature Reviews. Disease Primers. 2016;2(1):p. 16065. doi: 10.1038/nrdp.2016.65.
3. Zhong X, Chen Y, Chen W, Liu Y, Gui S, Pu J, et al. Identification of potential biomarkers for Major Depressive Disorder: based on integrated bioinformatics and clinical validation. Mol Neurobiol. 2024 May 9. doi:10.1007/s12035-024-04217-1.
4. Kong X, Wang C, Wu Q, et al. Screening and identification of key biomarkers of depression using bioinformatics. Sci Rep. 2023;13:4180. doi:10.1038/s41598-023-31413-1
5. Gururajan A, Naughton ME, Scott KA, O'Connor RM, Moloney G, Clarke G, Dowling J, Walsh A, Ismail F, Shorten G, Scott L, McLoughlin DM, Cryan JF, Dinan TG. MicroRNAs as biomarkers for major depression: a role for let-7b and let-7c. Transl Psychiatry. 2016 Aug 2;6(8):e862. doi: 10.1038/tp.2016.131. PMID: 27483380; PMCID: PMC5022079.
6. Kaurani L. Clinical insights into microRNAs in depression: bridging molecular discoveries and therapeutic potential. Int J Mol Sci. 2024;25(5):2866. Available from: https://doi.org/10.3390/ijms25052866
7. Zhao C, Sun G, Li S, Lang MF, Yang S, Li W, Shi Y. MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1876-81. doi: 10.1073/pnas.0908750107. PMID: 20133835; PMCID: PMC2836616.
8. Roumans S, Sundquist K, Memon AA, Hedelius A, Sundquist J, Wang X. Association of circulating let-7b-5p with major depressive disorder: a nested case-control study. BMC Psychiatry. 2021 Dec 9;21(1):616. doi: 10.1186/s12888-021-03621-4. PMID: 34886843; PMCID: PMC8662878.
9. Gururajan A, Naughton ME, Scott KA, O'Connor RM, Moloney G, Clarke G, Dowling J, Walsh A, Ismail F, Shorten G, Scott L, McLoughlin DM, Cryan JF, Dinan TG. MicroRNAs as biomarkers for major depression: a role for let-7b and let-7c. Transl Psychiatry. 2016 Aug 2;6(8):e862. doi: 10.1038/tp.2016.131. PMID: 27483380; PMCID: PMC5022079.
10. National library of Medicine. MAPK3 mitogen-activated protein kinase 3 [Homo sapiens (human)] Gene ID: 5595, updated on 17-Jun-2024 https:// www . ncbi . nlm . nih .gov /gene /5595 #gene -expression
11. National library of Medicine. PLA2G4F phospholipase A2 group IVF [ Homo sapiens (human)]GeneID:255189,updated on 17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/255189
12. National library of Medicine.PLA2G4B phospholipaseA2groupIVB[Homo sapiens (human)]GeneID:100137049,updatedon17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/100137049
13. National library of Medicine. GNAZ G protein subunit alpha z [ Homo sapiens (human) ] Gene ID: 2781, updated on 21-Jun-2023. https://www.ncbi.nlm.nih.gov/gene/2781
14. National library of Medicine. PLA2G4C phospholipase A2 group IVC [ Homo sapiens (human) ]Gene ID: 8605, updated on 17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/8605#top
15. National library of Medicine. CACNA1A calcium voltage-gated channel subunit alpha1 A [ Homo sapiens (human) ]Gene ID: 773, updated on 17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/773#top
16. National library of Medicine. GNA12 G protein subunit alpha 12 [ Homo sapiens (human) ]Gene ID: 2768, updated on 17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/2768
17. National library of Medicine. ITPR3 inositol 1,4,5-trisphosphate receptor type 3 [ Homo sapiens (human) ]Gene ID: 3710, updated on 17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/3710
18. National library of Medicine. ITPR1 inositol 1,4,5-trisphosphate receptor type 1 [ Homo sapiens (human)]Gene ID: 3708, updated on 17-Jun-2024https://www.ncbi.nlm.nih.gov/gene/3708
19. National library of Medicine. GUCY1A1 guanylate cyclase 1 soluble subunit alpha 1 [ Homo sapiens (human) ]Gene ID: 2982, updated on 17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/2982
20. National library of Medicine. GRID2 glutamate ionotropic receptor delta type subunit 2 [ Homo sapiens (human) ] https://www.ncbi.nlm.nih.gov/gene/2895Gene ID: 2895, updated on 17-Jun-2024
21. National library of Medicine. MAP2K2 mitogen-activated protein kinase kinase 2 [ Homo sapiens (human) ]Gene ID: 5605, updated on 17-Jun-2024 https://www.ncbi.nlm.nih.gov/gene/5605
22. Li X, Teng T, Yan W, et al. AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models. Transl Psychiatry. 2023;13:200. doi:10.1038/s41398-023-02486-3. Available from: https://www.nature.com/articles/s41398-023-02486-3#citeas
23. Wu Z, You Z, Chen P, Chen C, Chen F, Shen J, et al. Matrine exerts antidepressant-like effects on mice: Role of the hippocampal PI3K/Akt/mTOR signaling. Int J Neuropsychopharmacol. 2018;21:764–76.
24. Yang SJ, Song ZJ, Wang XC, Zhang ZR, Wu SB, Zhu GQ. Curculigoside facilitates fear extinction and prevents depression-like behaviors in a mouse learned helplessness model through increasing hippocampal BDNF. Acta Pharm Sin. 2019;40:1269–78.
25. Oh DR, Yoo JS, Kim Y, Kang H, Lee H, Lm SJ, et al. Vaccinium bracteatum Leaf extract reverses chronic restraint stress-induced depression-like behavior in mice: Regulation of hypothalamic-pituitary-adrenal axis, serotonin turnover systems, and ERK/Akt phosphorylation. Front Pharm. 2018;9:604.
26. Liaqat H, Parveen A, Kim SY. Antidepressive effect of natural products and their derivatives targeting BDNF-TrkB in gut-brain axis. Int J Mol Sci. 2022;23:14968.
27. Regulska M, Szuster-Głuszczak M, Trojan E, Leśkiewicz M, Basta-Kaim A. The Emerging Role of the Double-Edged Impact of Arachidonic Acid- Derived Eicosanoids in the Neuroinflammatory Background of Depression. Curr Neuropharmacol. 2021;19(2):278-293. doi: 10.2174/1570159X18666200807144530. PMID: 32851950; PMCID: PMC8033972.
28. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog. Neuropsychopharmacol. Biol. Psychiatry. 1995;19(1):11–38. doi: 10.1016/0278-5846(94)00101-M.
29. Maes M., Yirmyia R., Noraberg J., Brene S., Hibbeln J., Perini G., Kubera M., Bob P., Lerer B., Maj M. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab. Brain Dis. 2009;24(1):27–53. doi: 10.1007/s11011-008-9118-1.
30. Dowlati Y., Herrmann N., Swardfager W., Liu H., Sham L., Reim E.K., Lanctôt K.L. A meta-analysis of cytokines in major depression. Biol. Psychiatry. 2010;67(5):446–457. doi: 10.1016/j.biopsych.2009.09.033.
31. Raison C.L., Capuron L., Miller A.H. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24–31. doi: 10.1016/j.it.2005.11.006.
32. Sethi R., Gómez-Coronado N., Walker A.J., Robertson O.D., Agustini B., Berk M., Dodd S. Neurobiology and therapeutic potential of cyclooxygenase-2 (cox-2) inhibitors for inflammation in neuropsychiatric disorders. Front. Psychiatry. 2019;10(September):605. doi: 10.3389/fpsyt.2019.00605.
33. McCorvy JD, Roth BL. Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther. 2015 Jun;150:129-42. doi: 10.1016/j.pharmthera.2015.01.009. Epub 2015 Jan 17. PMID: 25601315; PMCID: PMC4414735.
34. Yang D, et al. G protein-coupled receptors: structure- and function-based drug discovery. Signal Transduct Target Ther. 2021;6:7.
35. Nido GS, Ryan MM, Benuskova L, Williams JM. Dynamical properties of gene regulatory networks involved in long-term potentiation. Front Mol Neurosci. 2015 Aug 7;8:42. doi: 10.3389/fnmol.2015.00042. PMID: 26300724; PMCID: PMC4528166.
36. Gambardella J, Lombardi A, Morelli MB, Ferrara J, Santulli G. Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update. J Clin Med. 2020 Apr 12;9(4):1096. doi: 10.3390/jcm9041096. PMID: 32290556; PMCID: PMC7231134.
37. Wu W, Howard D, Sibille E, French L. Differential and spatial expression meta-analysis of genes identified in genome-wide association studies of depression. Transl Psychiatry. 2021;11:8. Available from: https://www.nature.com/articles/s41398-020-01127-3.
38. Xiao Y, Luo H, Yang WZ, Zeng Y, Shen Y, Ni X, Shi Z, Zhong J, Liang Z, Fu X, Tu H, Sun W, Shen WL, Hu J, Yang J. A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics. Front Cell Neurosci. 2020 Apr 7;14:48. doi: 10.3389/fncel.2020.00048. PMID: 32317933; PMCID: PMC7156020.
39. Sabatini MJ, Ebert P, Lewis DA, Levitt P, Cameron JL, Mirnics K. Amygdala gene expression correlates of social behavior in monkeys experiencing maternal separation. J Neurosci. 2007 Mar 21;27(12):3295-304. doi: 10.1523/JNEUROSCI.4765-06.2007. PMID: 17376990; PMCID: PMC6672470.
40. Stevenson J.M. Reilly J.L. Harris M.S.H. Patel S.R. Weiden P.J. Prasad K.M.et al. Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes.Transl Psychiatry. 2016; 6 https://doi.org/10.1038/tp.2016.10
41. Allen JP, Garber KB, Perszyk R, Khayat CT, Kell SA, Kaneko M, Quindipan C, Saitta S, Ladda RL, Hewson S, et al. Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants. Hum Mol Genet. 2024;33(4):355-373. https://doi.org/10.1093/hmg/ddad188