Dysregulation of schizophrenia-associated genes and genome-wide hypomethylation in neurons overexpressing DNMT1

Lay abstract DNMT1 controls cytosine methylation, which is often associated with reduced gene expression. Increased levels of DNMT1 is a risk factor for schizophrenia but information on the affected genes is limited. In this study, similar to 50% of genes with altered levels of messenger RNAs in schizophrenia patients were also altered in neurons with increased DNMT1. Surprisingly, the neurons with higher DNMT1 levels showed genome-wide decrease in methylation. These findings uncover a new type of gene dysregulation that is independent of DNMT1's catalytic activity. Aim: To study the effects of DNMT1 overexpression on transcript levels of genes dysregulated in schizophrenia and on genome-wide methylation patterns. Materials & methods: Transcriptome and DNA methylome comparisons were made between R1 (wild-type) and Dnmt1(tet/tet) mouse embryonic stem cells and neurons overexpressing DNMT1. Genes dysregulated in both Dnmt1(tet/tet) cells and schizophrenia patients were studied further. Results & conclusions: About 50% of dysregulated genes in patients also showed altered transcript levels in Tet/Tet neurons in a DNA methylation-independent manner. These neurons unexpectedly showed genome-wide hypomethylation, increased transcript levels of Tet1 and Apobec 1-3 genes and increased activity and copy number of LINE-1 elements. The observed similarities between Tet/Tet neurons and schizophrenia brain samples reinforce DNMT1 overexpression as a risk factor.

Automated summary

About 50% of dysregulated genes in schizophrenia patients also showed altered transcript levels in neurons with increased DNMT1, independently of DNA methylation. These neurons unexpectedly exhibited genome-wide hypomethylation, along with increased transcript levels of Tet1 and Apobec 1-3 genes, as well as increased activity and copy number of LINE-1 elements. The similarities observed between these neurons and schizophrenia brain samples suggest that DNMT1 overexpression could be a risk factor for schizophrenia.