An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions

Abstract

Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer's or Parkinson's disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.

Keywords: DNA; brain; development; epigenetics; histones; neurodegeneration; neurons.

Figure 2

Histone tail epigenetic modifications described in the brain. All core histone proteins contain intrinsically disordered tail regions that protrude from the DNA-enveloped core and are known to play critical roles in chromatin regulation (see text). The linker histone H1 has a three-domain structure consisting of a short N-terminal tail, a central globular domain, and a long, extremely basic C-terminal tail [104]. Only the N-terminal tail is shown here. Aminoacidic residues are indicated by one-letter notation [71]. Amino lysine acid residues (K) undergoing epigenetic changes so far described in the old brain are indicated in red font. Sequences specific to H2AX are indicated by light orange circles. Abbreviations: AC = acetylation; Cr = crotonylation; Las = lactylation; Me = methylation; P = phosphorylation; Ser = serotonylation; Su = sumoylation; and Ub = ubiquitination. Created with BioRender.com.

Figure 1

Schematic representation of the three main groups of epigenetic modifications in mammalian cells: DNA methylation, histone epigenetic modifications, and non-coding RNAs. DNA methylation acts as an off-switch to block translation and occurs at CpG sites that are observed across the genome. Methylation can occur in intergenic regions, CpG islands, and the gene body. Nevertheless, CpG islands that are considered normal exhibit a lack of methylation throughout all stages of development. This lack of methylation enables the transcription of the specific gene, provided that the necessary transcription factors are present, and the chromatin structure is accessible to these factors. Histone modifications are chemical alterations, which can have profound effects on gene expression and, consequently, various cellular processes. These modifications form an epigenetic code that imparts a distinct feature on chromatin architecture. The enzymes that catalyze these modifications can be classified as writers, readers, and erasers. Writers are enzymes that are responsible for the acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation of histones. Among them, KMTs and HATs are of relevance. Readers are responsible for the recognition of the epigenetic marks on histones. Among readers are the readers of methyl- and acetyl-lysine residues. Among erasers are histone demethylases and deacetylases. Non-coding RNAs are divided into short and long non-coding RNAs. For simplicity, only the miRNA generation pathway is represented. Non-coding RNAs can interact with DNA, RNA, and protein molecules to modulate gene transcription, contribute to RNA inhibition or degradation, or serve as molecular guides, scaffolds, or decoys for specific proteins, such as transcription factors. These many functions occur either in the nucleus or the cell cytoplasm. Abbreviations: AC = acetylation; Ex = exon; lncRNA = long non-coding RNA; Me = methylation, demethylation, or trimethylation; miRNA = microRNA; NXF1 = nuclear RNA export factor 1; pre-miRNA; precursor miRNApri-mi RNA = hairpin-containing primary transcripts; Su = sumoylation; and XPO5 = exportin 5. Created with BioRender.com.