Epigenetics – its putative role in psychiatric conditions, such as schizophrenia

Professor Binder described a series of experiments to determine the effects of glucocorticoids (GC) on human fetal hippocampal progenitor cells (HFC).¹

Prenatal exposure to glucocorticoids might possibly prime vulnerability to stressful events later in life

Early exposure to GC produces long-lasting changes to DNA methylation within these cells. This effect can be likened to a priming effect, because subsequent exposure to GC produces a significantly elevated transcriptional response among certain genes. Thus, initial DNA methylation changes appear to make the cells vulnerable to further exposure to stressful events – just as prenatal exposure to GC might possibly prime vulnerability to stressful events later in life.

DNA methylation changes appear to make hippocampal progenitor cells vulnerable to further exposure to stressful events

Similar effect of glucocorticoids in cord blood

A similar response to GC exposure to that seen in HFC can also be seen in cord blood cells. By comparing markers of DNA methylation changes in cord blood and HFC, approximately 500 common sites were identified. An epigenome-wide association study (EWAS) of anxiety, depression or exposure to GC saw enrichment for these same common sites; suggesting alterations in DNA methylation might be associated with these psychiatric conditions.

Nature or nurture? It’s both!

Is it solely the maternal environment that’s determining this susceptibility to GC? From studies in which the relative effects of prenatal environment and genotype on DNA methylation could be ascertained, it appears that both influence susceptibility to complex disease risk, including risk of schizophrenia, in later life.³

Environmental and genetic effects both influence susceptibility to complex disease risk, including schizophrenia, in later life

So, what are the impacts of GC exposure on brain development? Work on cerebral forebrain organoids (artificially grown, in vitro, miniature organs resembling the brain) has given valuable insight into this question.⁴

Glucocorticoids in neurodevelopment and its disruption

Cerebral organoids express functional GC receptors (GCRs) which induce GC receptive genes. Three different organoids were exposed to GC and in each the differential expression of genes activated via GCRs in neurons, neural progenitors and non-neural progenitor cells was examined. In all cases, transcripts common to the developing cells from each organoid were enriched for factors involved in brain development and DNA binding. From further screening against a human Genome-wide Association Studies catalogue for traits related to brain and behavior, it became apparent that these transcripts were mainly associated with neuronal disorders.

ZBTB16 – Glucocorticoid receptor transcription factor of interest

Does GC exposure have an impact on neural progenitor differentiation? Work involving ZBTB16 – a GC receptor transcription factor expressed in cerebral organoids suggests that it does.

GC induces changes in DNA methylation in ZBTB16 in fetal brain cells indicating that ZBTB16 is an environmentally-responsive risk factor. It is also a genetic risk factor; rare genetic variants are associated with mental retardation and educational attainment.

Glucocorticoid receptor transcription factor, ZBTB16, is both an environmentally-responsive and a genetic risk factor

In vitro, ZBTB16 is expressed early in organoid development and its effects at this time are vitally important in progenitor development and differentiation. Disruption to its proper functioning disrupts proper progenitor migration. Furthermore, in animal models, it has also been seen that disruption through overstimulation of ZBTB16 late in embryonic gestation disrupts both progenitor cell migration and cortical structural organization.

Theoretically…

From the data gathered so far, models of fetal stress and its associated risk to later mental wellbeing can be postulated. Thus, in utero GC exposure could change the epigenetic landscape of ZBTB16 - or other as yet unknown neural transcription factors - leaving them primed. Additional stress further alters their profiles by, for instance, keeping them active when they should not be, thereby influencing the profile of neurocortical development. This, in turn, could lead to neurodevelopmental or psychiatric problems later in life.

The intriguing question now is - what are ZBTB16’s target genes?