Evaluating Gene Expression and Methylation Profiles of TCF4, MBP, and EGR1 in Peripheral Blood of Drug-Free Patients with Schizophrenia: Correlations with Psychopathology, Intelligence, and Cognitive Impairment

Overview

Journal J Mol Neurosci

Specialties Molecular Biology
Neurology

Date 2023 Sep 5

PMID 37668894

Authors

Fatemeh Yazarlou

Mobina Tabibian

Asaad Azarnezhad

Habib Sadeghi Rad

Leonard Lipovich

Golshid Sanati

Hamid Mostafavi Abdolmaleky

Fatemeh Alizadeh

Affiliations

Soon will be listed here.

Abstract

Discovery and validation of new, reliable diagnostic and predictive biomarkers for schizophrenia (SCZ) are an ongoing effort. Here, we assessed the mRNA expression and DNA methylation of the TCF4, MBP, and EGR1 genes in the blood of patients with SCZ and evaluated their relationships to psychopathology and cognitive impairments. Quantitative real-time PCR and quantitative methylation-specific PCR methods were used to assess the expression level and promoter DNA methylation status of these genes in 70 drug-free SCZ patients and 72 healthy controls. The correlation of molecular changes with psychopathology and cognitive performance of participants was evaluated. We observed downregulation of TCF4 and upregulation of MBP mRNA levels in SCZ cases, relative to controls in our study. DNA methylation status at the promoter region of TCF4 demonstrated an altered pattern in SCZ as well. Additionally, TCF4 mRNA levels were inversely correlated with PANSS and Stroop total errors and positively correlated with WAIS total score and working memory, consistent with previous studies by our group. In contrast, MBP mRNA level was significantly positively correlated with PANSS and Stroop total errors and inversely correlated with WAIS total score and working memory. These epigenetic and expression signatures can help to assemble a peripheral biomarker-based diagnostic panel for SCZ.

References

Abdolmaleky H, Pajouhanfar S, Faghankhani M, Joghataei M, Mostafavi A, Thiagalingam S . Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and Psychotic bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2015; 168(8):687-96. DOI: 10.1002/ajmg.b.32361. View

Alizadeh F, Tavakkoly-Bazzaz J, Bozorgmehr A, Azarnezhad A, Tabrizi M, Ananloo E . Association of transcription factor 4 (TCF4) gene mRNA level with schizophrenia, its psychopathology, intelligence and cognitive impairments. J Neurogenet. 2017; 31(4):344-351. DOI: 10.1080/01677063.2017.1396330. View

Baruch K, Silberberg G, Aviv A, Shamir E, Bening-Abu-Shach U, Baruch Y . Association between golli-MBP and schizophrenia in the Jewish Ashkenazi population: are regulatory regions involved?. Int J Neuropsychopharmacol. 2009; 12(7):885-94. DOI: 10.1017/S1461145708009887. View

Brzozka M, Radyushkin K, Wichert S, Ehrenreich H, Rossner M . Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain. Biol Psychiatry. 2010; 68(1):33-40. DOI: 10.1016/j.biopsych.2010.03.015. View

Cattane N, Minelli A, Milanesi E, Maj C, Bignotti S, Bortolomasi M . Altered gene expression in schizophrenia: findings from transcriptional signatures in fibroblasts and blood. PLoS One. 2015; 10(2):e0116686. PMC: 4319917. DOI: 10.1371/journal.pone.0116686. View

DRozario M, Zhang T, Waddell E, Zhang Y, Sahin C, Sharoni M . Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons. Cell Rep. 2016; 15(2):386-97. PMC: 4946342. DOI: 10.1016/j.celrep.2016.03.034. View

de Witte L, Wang Z, Snijders G, Mendelev N, Liu Q, Sneeboer M . Contribution of Age, Brain Region, Mood Disorder Pathology, and Interindividual Factors on the Methylome of Human Microglia. Biol Psychiatry. 2022; 91(6):572-581. PMC: 11181298. DOI: 10.1016/j.biopsych.2021.10.020. View

Du Y, Yu Y, Hu Y, Li X, Wei Z, Pan R . Genome-Wide, Integrative Analysis Implicates Exosome-Derived MicroRNA Dysregulation in Schizophrenia. Schizophr Bull. 2019; 45(6):1257-1266. PMC: 6811837. DOI: 10.1093/schbul/sby191. View

Du Y, Chen L, Li X, Li X, Xu X, Tai S . Metabolomic Identification of Exosome-Derived Biomarkers for Schizophrenia: A Large Multicenter Study. Schizophr Bull. 2020; 47(3):615-623. PMC: 8084447. DOI: 10.1093/schbul/sbaa166. View

10.

Duclot F, Kabbaj M . The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders. Front Behav Neurosci. 2017; 11:35. PMC: 5337695. DOI: 10.3389/fnbeh.2017.00035. View

11.

Forrest M, Chapman R, Doyle A, Tinsley C, Waite A, Blake D . Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. Hum Mutat. 2012; 33(12):1676-86. DOI: 10.1002/humu.22160. View

12.

Gejman P, Sanders A, Duan J . The role of genetics in the etiology of schizophrenia. Psychiatr Clin North Am. 2010; 33(1):35-66. PMC: 2826121. DOI: 10.1016/j.psc.2009.12.003. View

13.

Gouvea-Junqueira D, Falvella A, Antunes A, Seabra G, Brandao-Teles C, Martins-de-Souza D . Novel Treatment Strategies Targeting Myelin and Oligodendrocyte Dysfunction in Schizophrenia. Front Psychiatry. 2020; 11:379. PMC: 7203658. DOI: 10.3389/fpsyt.2020.00379. View

14.

Gutierrez-Fernandez A, Gonzalez-Pinto A, Vega P, Barbeito S, Matute C . Expression of oligodendrocyte and myelin genes is not altered in peripheral blood cells of patients with first-episode schizophrenia and bipolar disorder. Bipolar Disord. 2010; 12(1):107-9. DOI: 10.1111/j.1399-5618.2009.00776.x. View

15.

Hendrickx A, Pierrot N, Tasiaux B, Schakman O, Kienlen-Campard P, De Smet C . Epigenetic regulations of immediate early genes expression involved in memory formation by the amyloid precursor protein of Alzheimer disease. PLoS One. 2014; 9(6):e99467. PMC: 4053420. DOI: 10.1371/journal.pone.0099467. View

16.

Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge T . Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register. Biol Psychiatry. 2017; 83(6):492-498. DOI: 10.1016/j.biopsych.2017.08.017. View

17.

Hu T, Chen S, Hsu S, Cheng M . Functional analyses and effect of DNA methylation on the EGR1 gene in patients with schizophrenia. Psychiatry Res. 2019; 275:276-282. DOI: 10.1016/j.psychres.2019.03.044. View

18.

Kinoshita M, Numata S, Tajima A, Shimodera S, Ono S, Imamura A . DNA methylation signatures of peripheral leukocytes in schizophrenia. Neuromolecular Med. 2012; 15(1):95-101. DOI: 10.1007/s12017-012-8198-6. View

19.

Li L, Dahiya R . MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002; 18(11):1427-31. DOI: 10.1093/bioinformatics/18.11.1427. View

20.

Liu Q, Li S, Dupuy A, Mai H, Sailliet N, Loge C . Exosomes as New Biomarkers and Drug Delivery Tools for the Prevention and Treatment of Various Diseases: Current Perspectives. Int J Mol Sci. 2021; 22(15). PMC: 8346134. DOI: 10.3390/ijms22157763. View