User:Vale028/sandbox/Week 4

The objective is to edit the Wikipedia articles Epigenetics of Schizophrenia and Behavioral Epigenetics.

Epigenetics of Schizophrenia:
The Epigenetics of Schizophrenia article needs updating. The article briefly discusses a few epigenetic components that are implicated with schizophrenia .Since the article was published, there has been a surge of new research on this topic. With the current understanding of schizophrenia, the article can be significantly improved. In this proposal, I will address new research that can be added to the article.

Research has found that schizophrenia is implicated with three epigenetic modulations: methylation of DNA, non-coding RNA (ncRNA)  transcriptional regulation,and histone modification. DNA methylation is the most studied epigenetic modulation. In schizophrenia research, DNA hypermethylation has been discovered as a possible cause for the disorder. Research on DNA hypermethylation is vast and there is plenty of new information that can be included in the article. For instance, DNA hypermethylation has been identified in 3 CpG sites in serotonin receptor 2A and in 2 CpG sites in the promoter of glutamic acid decarboxylase 1 (GAD1). GAD1 is an enzyme that regulates the production of GABA and is suppressed by hypermethylation at its promoter site in the frontal and prefrontal cortex. To add, reelin (RELN) is suppressed by hypermethylation at its promoter site in the frontal and prefrontal cortex. Suicidal ideation in schizophrenics is correlated to hypermethylation in CpG in the SLC20A1 gene.

In addition, DNA hypomethylation has been linked to schizophrenia. DNA hypomethylation has been identified in the promoter region of the COMT gene in the frontal lobe (COMT methylation is correlated to predict schizophrenia risk in males). Hypomethylation of MMP9 has been associated with the negative symptoms of schizophrenia. DNA hypomethylation of MMP9 is seen in deficit   schizophrenia (restricted affect/ emotional range, have at least 2/6 negative symptoms) patients compared to non-deficit schizophrenia patients. Other genes with DNA hypomethylation in schizophrenic patients include: “ AluY A3 CpG, promoter of GRIN2B, CpG2 and CpG3 in TREM2 intron 1, CpG sites in FAM63B and intergenic region on chromosome 16, CpG sites in TBC1D22A” (Chen et al., 2021).

The effects of DNA methylation may be sex specific. In females, methylation of oxytocin receptors are negatively correlated to negative symptoms of schizophrenia (anhedonia).

Furthermore, research has shown a relationship between ncRNA and schizophrenia, specifically microRNA (miRNA) and long chain non coding RNA (lncRNA). ncRNA research is new yet  miRNA’s have since been implicated in many mental disorders. There are many miRNA’s that are dysregulated in schizophrenia. Dysregulation of miR-137 is predictive of early onset psychosis. However, up regulation of miRNA is generally seen in schizophrenic groups compared to controls. There are 11 miRNA’s that may indicate the presence of the disorder. Some of the miRNA’s are associated with treatment efficacy and responsiveness (miR-21, miR-195 decrease with antipsychotics and olanzapine treatment, respectively). Below is the link to a table of  all the miRNA dysregulations found in schizophrenia (it’s too much to add here): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8334178/table/T1/?report=objectonly. Additionally, lncRNA may also be a marker of Schizophrenia and predict responsiveness to treatment. Upregulation of 62 lncRNA and downregulation of 63 lncRNAs have been identified in schizophrenia compared to controls. The dysregulation of lncRNA cause the downregulation of genes like  FAS-AS1, PVT1, TUG1, Neat1 and Neat2 and upregulation of THRIL. Below is a table of lncRNA and gene dysregulations: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8334178/table/T2/?report=objectonly

Currently, histone modification is poorly linked to schizophrenia. Some research has shown that acetylation of H3 at genes GAD78, TOMM70A, HTR2C, and PPM1E (schizophrenia-linked genes) correlates with their expression.

Moreover, several of the epigenetic modulations that occur in schizophrenia are present in other mental disorders and are not discussed in the wikepedia article. For instance, DNA methylation abnormalities have been associated with neurodevelopmental disorders like schizophrenia and autism. Genes linked to these disorders include DRD2, SOX10, NRXN1 and are methylated depending on age. Abnormalities in these methylations are present in these neurodevelopmental disorders. BDNF expression and methylation is linked to several mental disorders including depression, schizophrenia, autism, bipolar disorder. Methylation of GAD1 is similarly seen between schizophrenia and bipolar disorder in the hippocampus. lncRNAs dysregulates  the expression of target genes that may cause depression, schizophrenia, bipolar disorder, or other disorders. In fact, lncRNAs have a critical role in antidepressant treatment for depression.

In conclusion, there is an abundant amount of literature on schizophrenia. The Wikipedia article discusses several other aspects of the disorder that are not specific to epigenetics. However, those sections can also be updated. Research on twin studies, other psychotic/ mental disorders, and pharmacology  that tie in to the epigenetic modifications of schizophrenia would improve the article as well. Research on the link between GAD1, SOX10, COMT, RELN, 5HT1A, and BDNF should be included or discussed more thoroughly. The article does need huge work to update it to the current scientific knowledge which makes it a perfect article for this assignment.

Resource:

Chen Q, Li D, Jin W, Shi Y, Li Z, Ma P, Sun J, Chen S, Li P, Lin P. Research Progress on the Correlation Between Epigenetics and Schizophrenia. Front Neurosci. 2021 Jul 21;15:688727. doi: 10.3389/fnins.2021.688727. PMID: 34366776; PMCID: PMC8334178.

Nestler EJ, Peña CJ, Kundakovic M, Mitchell A, Akbarian S. Epigenetic Basis of Mental Illness. Neuroscientist. 2016 Oct;22(5):447-63. doi: 10.1177/1073858415608147. Epub 2015 Oct 8. PMID: 26450593; PMCID: PMC4826318.

Behavioral Epigenetics Edits:
This article can be updated by new scientific research.

Bipolar disorder
Several studies have found causality between epigenetic modulations and bipolar disorder. For instance, DNA methylation of the HLA9 and GAD1 gene has been identified in patients with bipolar disorder. The DNA methylation that occurs on GAD1 gene in the hippocampus of patients with bipolar disorder is similar to the pattern found in schizophrenia. Similarly, a regulator of H3K4 methylation has been strongly linked to bipolar disorder and other psychosis related disorders.

Depression

Research on the epigenetics of depression is more extensive. For example, hypermethylation of NR3C1 in the hippocampus has been linked to high stress levels in newborns with depressed mothers, in children who are separated from their parents, and in children who experience low parental care. NR3C1 was under expressed in people who committed suicide and experienced child abuse compared to a control of people who committed suicide but were not abused.

These are some examples of information that can be added to the wiki article. There is a growing body of research on all the topics covered in this article that can be used to update the article. The epigenetics of depression and bipolar disorder was of the most interest to me. However, the article covers a wide range of topics which makes it a perfect article for this project because there is plenty to expand on.

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826318/#R53