Histone Acetylation and its Role in Mental Illnesses

Post by Leanna Kalinowski

Exploring the epigenetic mechanisms of mental illnesses is a promising avenue for better understanding how these disorders develop and can be treated. The vast majority of mental illnesses are attributed to a combination of genetic and environmental factors. By studying their epigenetic mechanisms – including histone acetylation – we can gain a better understanding of how our environment influences the expression of our genes to influence the development of mental illnesses.

What are histones and how are they organized?

If you were to unravel all the DNA contained within a single human cell, it would be nearly six feet long – taller than the average human adult! With our cells containing so much DNA, there is a uniform biological system for packing it tightly enough so that it fits within the cell’s nucleus without becoming tangled – a system that relies on tiny proteins called histones. 

Histones are organized into nucleosomes, which each contain eight histones – two of each of the four histone subtypes (i.e., H2A, H2B, H3, and H4). Think of each nucleosome as a spool, and DNA like a strand of yarn. Our DNA tightly wraps itself around each nucleosome, which then combine and condense into chromatin, which makes up our chromosomes. In addition to this structural support, histones play a crucial role in determining whether genes are expressed. This has wide implications for nearly all aspects of our biology, including the development and treatment of mental illnesses.

How do histones impact gene expression?

The density of nucleosomes when they are packed into chromatin directly impacts whether a gene is transcribed (i.e., the first step in gene expression). When nucleosomes are tightly packed together, many of the genes within them cannot be transcribed; this type of chromatin is called heterochromatin. On the other hand, when nucleosomes are loosely packed together, their genes are much more accessible and able to be transcribed; this type of chromatin is called euchromatin. 

This overall arrangement of chromatin – and therefore the accessibility of genes to be transcribed – can be influenced by modifications to histones. Among the most well-known histone modifications are histone acetylation and deacetylation. During histone acetylation, an acetyl group is added to the histone tail, which leads to a relaxed chromatin structure (i.e., euchromatin) and greater accessibility for its genes to be transcribed. The opposite happens during histone deacetylation, where the acetyl group is removed, leading to a more densely packed chromatin structure (i.e., heterochromatin) and decreased ability for genes to be transcribed. These modifications are generally driven by two classes of enzymes: histone acetyltransferase (HATs), which acetylate histones, and histone deacetylase (HDACs), which deacetylate histones.

How does histone acetylation impact mental illnesses?

Several mental illnesses, along with their environmental risk factors, have been associated with changes in histone acetylation. In particular, histone acetylation has been implicated in the development of depression, anxiety, schizophrenia, and bipolar disorder. Further, a common risk factor for all these disorders – chronic stress – exerts widespread impacts on histone acetylation, particularly in limbic brain regions. Similarly, negative prenatal and early-life experiences, including prenatal stress, maternal separation, and child neglect, have been shown to increase HDAC expression in the prefrontal cortex. Taken together, these findings suggest promising avenues for future explorations into how mental illness impacts gene expression, particularly through histone acetylation. 

Another current direction in histone acetylation research is whether these mechanisms can be targeted as a treatment option, particularly for depression. HDAC inhibitors, which increase histone acetylation and therefore increase gene expression, show particular promise in treating depression in rodent models. For example, increasing histone acetylation has been associated with a reversal of the negative impacts following chronic stress and maternal separation. However, given that HDAC inhibitors can have widespread effects beyond just the brain, the authors of this work caution that therapeutic administration to humans will have unwanted and unintended consequences. Further research and drug development are needed to (1) selectively administer HDAC inhibitors to the human brain and (2) determine whether this is an effective treatment option for depression and other mental illnesses. 

References +

Abel & Zukin. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. (2008). Current Opinion in Pharmacology.

Chen et al. Research progress on the correlation between epigenetics and schizophrenia. (2021). Frontiers in Neuroscience.

Nestler. Epigenetic mechanisms of depression. (2014). JAMA Psychiatry.

Nestler et al. Epigenetic basis of mental illness. (2016). Neuroscientist.

Park et al. Epigenetic targeting of histone deacetylases in diagnostics and treatment of depression. (2021). International Journal of Molecular Sciences.

Sun et al. Epigenetics of the depressed brain: Role of histone acetylation and methylation. (2013). Neuropsychopharmacology.