The Placenta, OGT, Immune System and Autism

O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development.

http://www.ncbi.nlm.nih.gov/pubmed/23487789

Abstract

Maternal stress is a key risk factor for neurodevelopmental disorders, including schizophrenia and autism, which often exhibit a sex bias in rates of presentation, age of onset, and symptom severity.

The placenta is an endocrine tissue that functions as an important mediator in responding to perturbations in the intrauterine environment and is accessible for diagnostic purposes, potentially providing biomarkers predictive of disease.

Therefore, we have used a genome-wide array approach to screen placental expression across pregnancy for gene candidates that are sex-biased and stress-responsive in mice and translate to human tissue.

We identifed O-linked-N-acetylglucosamine (O-GlcNAc) transferase (OGT), an X-linked gene important in regulating proteins involved in chromatin remodeling, as fitting these criteria.

Levels of both OGT and its biochemical mark, O-GlcNAcylation, were significantly lower in males and further reduced by prenatal stress.

Examination of human placental tissue found similar patterns related to X chromosome dosage.

As a demonstration of the importance of placental OGT in neurodevelopment, we found that hypothalamic gene expression and the broad epigenetic microRNA environment in the neonatal brain of placental-specific hemizygous OGT mice was substantially altered.

These studies identified OGT as a promising placental biomarker of maternal stress exposure that may relate to sex-biased outcomes in neurodevelopment.

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Further Readings of Interest

Denitrosylation of S-nitrosylated OGT is triggered in LPS-stimulated innate immune response.

http://www.ncbi.nlm.nih.gov/pubmed/21453677

Abstract

O-linked N-acetylglucosaminyltransferase (OGT)-mediated protein O-GlcNAcylation has been revealing various aspects of functional significance in biological processes, such as cellular signaling and activation of immune system.

We found that OGT is maintained as S-nitrosylated form in resting cells, and its denitrosylation is triggered in innate immune response of lipopolysaccharide (LPS)-treated macrophage cells.

S-nitrosylation of OGT strongly inhibits its catalytic activity up to more than 80% of native OGT, and denitrosylation of OGT leads to protein hyper-O-GlcNAcylation. Furthermore, blockage of increased protein O-GlcNAcylation results in significant loss of nitric oxide and cytokine production. We propose that denitrosylation of S-nitrosylated OGT is a direct mechanism for upregulation of OGT activity by which immune defense is critically controlled in LPS-stimulated innate immune response.

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This entry was posted in Autism, Environment, Genetics, Gut, Immune System, Inflammation, Neurology, Physiology, Schizophrenia, Treatment. Bookmark the permalink.

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