Neuroepigenetics: Silent or Silenced?

Malleeka Suy

Neuroepigenetics…the word itself is a mouthful, but it doesn’t have to be a brainful. You probably know what “neuro” indicates, but what is “epigenetics”? 

Suppression and Amplification 

Contrary to popular belief, your genetics are not as static as you may think. Where you live and your life experiences can change how your genes are expressed. This is the field of epigenetics. These changes can express more or less of your genes, but the gene sequences themselves are not changed. These changes are achieved in many ways but generally involve the addition or removal of different chemical groups on genes with the help of certain proteins. DNA methylation, for example, utilizes enzymes called DNA methyltransferases (Dnmts) to attach a methyl group, or three hydrogens attached to a carbon, to DNA nucleotides (the building blocks of DNA) to “turn off” genes. Conversely, the process of histone acetylation “turns on” genes by attaching an acetyl group to a histone, the protein around which DNA is wound like a yo-yo. This “loosens” the DNA from the histone, allowing easier access for proteins and other factors to attach. Both methylation and acetylation are also reversible. Think of these processes as a light switch on our DNA!  

DNA methylation and histone acetylation are examples of epigenetic modifications. Methyl groups block gene readers, such as RNA Polymerase II (RNAPII), and other factors from binding to DNA and expressing genes. Acetyl groups “loosen” DNA and allow RNAPII and factors better access. Made on BioRender. 

In the Brain

Changing the expression of certain genes alters the amount of proteins being produced, which can affect how certain parts of our body function. Neuroepigenetics specifically focuses on how epigenetic modifications shape the development and functioning of the human nervous system and brain.

The development of the human central nervous system depends highly on DNA methylation and demethylation, or the removal of methyl groups from DNA. The foundations of the central nervous system are neurons, which are cells that signal your brain to think and move, and astrocytes, star-shaped cells that nourish neurons and support brain function (read here for more information on neurons, or here for more information on astrocytes). Both of these cells evolve from starter cells called neural progenitor cells—these NPCs first develop into neurons, then switch to develop into astrocytes (Qian et al, 2000; Sauvageot and Stiles, 2002). This switch is controlled by DNA methylation and demethylation of the glial fibrillary acidic protein (Gfap) gene via different Dnmts (Teter et al, 1994). Methylation of Gfap via Dnmt1 results in repressed expression, which correlates with neuron development (Teter et al, 1996; Takizawa et al, 2001; Fan et al, 2005). As you may have guessed, demethylation of Gfap thus corresponds with the development of astrocytes (Teter et al, 1996). 

Schematic of how methylation of Gfap plays a role in the development of neurons and astrocytes from neural progenitor cells (NPCs). Methylation of Gfap produces neurons, while demethylation of Gfap produces astrocytes. Made in BioRender.

Methylation also affects learning and memory formation. Protein phosphatase 1 (PP1) is a gene that suppresses learning and memory; methylating PP1, therefore producing less PP1,  allows for better memory maintenance, improves the efficacy of associative training, and enhances long-term potentiation (LTP), or the process of strengthening connections being made across brain cells (Genoux et al., 2002; Jouvenceau et al., 2006; Blitzere et al., 1998; Khan Academy). Subsequently, demethylation of the memory-promoting gene reelin suggests better memory maintenance and enhanced LTP (Miller and Sweatt, 2007). Methylation studies could thus play a huge role in memory retention, combatting aging and cognitive disorders. 

Too Much or Too Little?

Neuroepigenetics acts like the checks and balances of the brain, so errors can cause a cascade of serious complications. Too little methylation where methylation should occur can cause severe cognitive lapses and developmental defects. Mutations in the Dnmt1 gene, for example, can cause improper folding of the Dnmt1 protein, leading to decreased activity, faulty DNA binding, and imbalanced methylation levels, where certain areas are more methylated than others (Klein et al., 2011). Certain mutations within Dnmt1 have also been linked to hereditary, sensory, and autonomic neuropathy type 1 (HSAN1), a neurodegenerative disease that presents with dementia, loss of hearing, and loss of sensation in the feet and hands (Klein et al., 20111). Similarly, mutations in the Dnmt3a gene cause Tatton-Brown-Rahman Syndrome (TBRS), a rare overgrowth syndrome characterized by tall stature, an enlarged head, intellectual disabilities, and distinct facial features (Tibben and Rothbart, 2025; TBRS Community). But too much methylation can pose problems as well: An increase in Dnmt1 and Dnmt3a expression is linked to human temporal lobe epilepsy (TLE) and recurrent seizures (Zhu et al., 2012). 

Varied acetylation levels have also been associated with Alzheimer’s disease (AD), a common neurodegenerative disease that results in progressive memory loss. Plaques and tangles of a protein called tau in specific brain regions increase the risk of developing AD (Mattson, 2004; Ballatore et al., 2007). While histone acetylases add acetyl groups to histones to increase gene expression, histone deacetylases (HDACs) remove them, resulting in tighter DNA packaging around histones and reduced gene expression. In postmortem brain samples from AD patients, an increased level of HDAC6 correlated with an increase in tau levels (Cooke et al., 2012). Methylation and acetylation, and their opposites, are thus crucial for healthy development and function. 

Schematic comparing a healthy brain to one with Alzheimer’s. In healthy brains, tau proteins stabilize microtubules, which act as “train tracks” for nutrient transport and neuronal communication. In Alzheimer’s brains, tau protein tangles form neurofibrillary tangles, collapsing the “tracks” and destabilizing the microtubules. Made in BioRender. 

The field of neuroepigenetics provides an exciting behind-the-scenes look at the development of the brain. Despite all that we know about the epigenetic mechanisms behind a healthy brain, it is not an easy fix. Epigenetics is a hotspot for hopes of treating diseases such as Alzheimer’s and neurological problems associated with aging. For more information on brain basics, Alzheimer’s, and more neuroscience topics, be sure to browse our other blogs! 

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