Age- and Sex-Related Expression of Epigenetic Enzymes in the Human Brain

Post by Amanda McFarlan

What's the science?

Histone deacetylases are a family of epigenetic enzymes often termed epigenetic regulators, as some members of the family can modify gene expression in response to environmental and genetic cues. Preclinical and post-mortem studies in humans have shown that dysregulation of these enzymes may be associated with neurodegenerative diseases. Additionally, it has been suggested that sex-related differences in histone deacetylase expression may account for the discrepancy in the prevalence of neurodegenerative disorders between males and females. This week in Nature Communications, Gilbert, Zurcher and colleagues used neuroimaging techniques to investigate the role of sex and aging on the expression of histone deacetylase in the human brain.

How did they do it?

The authors used simultaneous magnetic resonance imaging (MRI) and positron emission tomography (PET) to map the expression of histone deacetylases in the brains of 41 healthy male and female participants aged 18 to 79 years old. They used 11C Martinostat (selective for class-I histone deacetylases) as the radiotracer for the PET scan and used the standard uptake value normalized to the whole brain mean as the measure of radiotracer uptake in the brain. They used a voxel-wise analysis (an analysis that examines each voxel or pixel in the brain) to investigate the correlational relationship between radiotracer uptake (indicative of histone deacetylase expression) and age or sex. Additionally, they calculated the generalized fractional anisotropy (a measure of the structural organization of the brain’s white matter) to determine whether age-related changes in histone deacetylase levels may be linked with white matter microstructure. Then, they used a voxel-wise analysis to look at the relationship between changes in histone deacetylase levels and white matter microstructure across the lifespan. Next, the authors used post mortem human brain tissue from 9 older individuals (average age of 85 years) and 9 younger individuals (average age of 18 years) of both sexes to investigate age-related changes in histone deacetylase expression at the molecular level. They assessed the relative protein expression levels of histone deacetylases 1, 2, 3, and 6 in the white matter using western blots.

The authors also explored how changes in histone deacetylase expression across the lifespan affect human behaviour. To do this, they assessed 23 participants (both male and female, aged 23-79 years old) on the Mayer-Salovey-Caruso Emotional Intelligence Test and then performed voxel-wise analyses to determine the relationship between radiotracer uptake levels and emotional intelligence.

What did they find?

The authors found that the expression of histone deacetylase (measured by radiotracer uptake) increased with age in the cerebral white matter, but not in the corpus callosum or the hippocampus. Notably, they determined that the onset of this age-related increase in histone deacetylase occurred in mid-adulthood, around the age of 35 years old. The authors also showed that levels of histone deacetylase expression were higher in males compared to females in the cerebellar white matter and lower in males compared to females in the frontal medial cortex, amygdala, hippocampus, parahippocampal gyrus and thalamus. Together, these findings suggest that histone deacetylase exhibits both sex-related and age-related patterns of expression in the brain. Additionally, the authors determined that age-related increases in histone deacetylase expression levels were associated with decreases in white matter microstructure, suggesting that increased histone deacetylase expression may be linked to degeneration of white matter. Next, the authors found that expression levels of histone deacetylases 1 and 2 (important for myelination and oligodendrocyte differentiation) were significantly higher in tissue from older individuals compared to younger individuals. Conversely, there were no observable age-related differences in the expression levels of histone deacetylases 3 and 6. Together, these findings suggest that increased expression of histone deacetylases 1 and 2, but not 3 and 6, are likely responsible for the observed increase in histone deacetylase across the lifespan.

Finally, the authors revealed that histone deacetylase expression levels in the hippocampus, as well as the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus tracts (important for social cognition and theory of mind),  were negatively correlated with emotional intelligence scores, suggesting that age-related increases in epigenetic changes in these brain regions may have a negative impact on emotional cognitive performance. 

What's the impact?

This is the first study to show that the expression of histone deacetylase in the human brain differs between sexes and increases across the lifespan. Additionally, the authors revealed that increased histone deacetylase expression in the hippocampus and white matter may negatively affect behaviour. Since histone deacetylase expression is known to be implicated in disease risk, these findings provide insight into how they may be used as an ideal target for the development of treatments to prevent or interrupt disease progression.

Gilbert et al. Neuroepigenetic signatures of age and sex in the living human brain. Nature Communications (2019). Access the original scientific publication here.