Dysregulation of Schizophrenia-Associated Genes and Genome-Wide Hypomethylation in Neurons Overexpressing DNMT1

Abstract

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.

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, ∼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.

Graphical abstract

Keywords::

• DNMT1 overexpression
• genome-wide hypomethylation
• LINE-1 burden
• schizophrenia
• transcript dysregulation

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0133

Author contributions

The experiments were designed and executed and the data were analyzed by S Choudhury, S Saxena and KN Mohan. PA Maroju carried out real-time PCR assays for a few SZ-associated genes, demethylation promoting genes and repeat elements. A Anne and L Kumar participated in the bioinformatic analyses. S Choudhury and KN Mohan wrote the manuscript.

Acknowledgments

The authors thank M Singh and T Jamma for their help during the experimental procedures.

Financial & competing interests disclosure

This work was supported by grants from Scientific and Engineering Research Board (SERB) Government of India and OPERA (BITS Pilani) during initial phase and by Centre for Human Disease Research (BITS Pilani) in the later phase. S Saxena was supported by a fellowship from a grant from Department of Biotechnology, Government of India. S Choudhury, A Anne and PA Maroju are supported by Centre for Human Disease Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by grants from Scientific and Engineering Research Board (SERB) Government of India and OPERA (BITS Pilani) during initial phase and by Centre for Human Disease Research (BITS Pilani) in the later phase. S Saxena was supported by a fellowship from a grant from Department of Biotechnology, Government of India. S Choudhury, A Anne and PA Maroju are supported by Centre for Human Disease Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.