Developmental vitamin D deficiency increases DNA methylation in embryonic mesencephalon — The Association Specialists
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Developmental vitamin D deficiency increases DNA methylation in embryonic mesencephalon (21977)

Xiaoying Cui 1 2 , Renata Pertile 1 , Paul Marshall 3 , Darryl Eyles 1 2 , Suzy Alexander 1 2 , Asad Ali 1
  1. Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
  2. Queensland Centre for Mental Health Research, Wacol, QLD, Australia
  3. ANU College of Health and Medicine, Canberra, ACT 2601

Schizophrenia, a complex neurodevelopmental disorder, is characterized by aberrant dopamine neurotransmission. Previous research has established a link between developmental vitamin D (DVD) deficiency and an increased risk of schizophrenia in humans. Our rodent model further supports this association, demonstrating impaired dopamine neuron maturation. Given vitamin D’s role in DNA methylation, a critical epigenetic regulator, we investigated its potential involvement in dopamine development.

We observed a selective upregulation of a DNA methyltransferase (DNMT3A) from a panel of DNA methylation enzymes in the embryonic day 14 mesencephalon of DVD-deficient embryos. In primary mesencephalic neural cultures, DNMT3A overexpression and silencing decreased and increased CCND1 (Cyclin D1) and CDKN1A (P21) expression, respectively, without altering dopamine-associated transcript expression. Furthermore, hypermethylation of the CCND1 and CDKN1A promoters was detected in DVD-deficient embryos. These findings suggest that DVD deficiency induces aberrant DNA methylation, impacting cell cycle regulation in the developing mesencephalon.

Our results provide evidence that DVD deficiency may contribute to the pathogenesis of schizophrenia by disrupting early brain development. The observed hypermethylation of cell cycle genes in the mesencephalon could underlie the delayed differentiation of dopaminergic neurons, ultimately leading to the long-term dopamine dysfunction characteristic of schizophrenia. Our study highlights the importance of vitamin D in early brain development and suggests a possible epigenetic mechanism by which DVD deficiency can contribute to schizophrenia.