Epigenetics, histone modification, DNA methylation, significance

Epigenetic mechanisms alter gene expression without changing the DNA sequence. They are crucial for regulating which genes are expressed, when, and to what extent.

The main types of epigenetic regulation include:

• DNA methylation
• Histone modifications
• X chromosome inactivation
• Genomic imprinting

DNA Methylation

DNA methylation is a transcription-repressing mechanism.

It is performed by DNA methyltransferases, which methylate cytosine residues to form 5-methylcytosine, primarily within CG dinucleotide sequences.

These CG sequences, often forming CpG islands, are typically found in promoter regions (most relevant for transcription regulation) and in first exons or coding regions.

DNA methylation is tightly linked to histone modifications, especially acetylation, and together they control chromatin structure.

Methylated DNA and histone deacetylation produce condensed chromatin, preventing RNA polymerase access.

During DNA replication, only the parental strand is methylated.

Methyltransferases detect hemimethylated DNA and methylate the daughter strand, preserving methylation patterns across generations.

Biological roles of DNA methylation:

• Regulation of tissue-specific gene expression
• X chromosome inactivation
• Genomic imprinting

Histone Modifications

Histones can undergo several post-translational modifications, including acetylation, methylation, and phosphorylation.

Each modification alters chromatin structure and transcriptional activity:

• Lysine methylation on histones usually represses transcription.
• Arginine methylation generally activates transcription.
• Phosphorylation of histone H1 correlates with chromosome condensation; dephosphorylation with decondensation.

acetylation

Acetylation plays a major role in gene activation:

• It neutralizes the positive charge of histones, loosening DNA-histone interactions.
• This creates open chromatin, allowing transcription to proceed.
• In inactive chromatin, histones are hypoacetylated, leading to tighter DNA binding.

These processes are catalyzed by:

• Histone acetyltransferases (HATs) – promote transcription
• Histone deacetylases (HDACs) – repress transcription

X Chromosome Inactivation

In females, around day 15 after fertilization, one of the two X chromosomes becomes inactivated to equalize gene dosage with males.

The inactivation is random in each cell, but permanent in its descendants. As a result, female tissues are mosaics, with some cells inactivating the maternal X and others the paternal X.

Regulation is controlled by the X-inactivation center, which includes:

• Xist gene (X-inactive specific transcript)
  • Produces a long non-coding RNA (~17 kb) that does not exit the nucleus, but binds and silences the same X chromosome it was transcribed from.

• Xce gene (X-controlling element)
  • Likely influences which X chromosome is inactivated.

Inactivated X chromosomes exhibit:

• Late replication timing
• Histone hypoacetylation
• DNA hypermethylation

Genomic Imprinting

Genomic imprinting results in monoallelic expression of certain genes—only one allele (maternal or paternal) is active, while the other is silenced.

The choice of which allele is silenced is not random; it depends on parental origin.

Imprinting may occur in all tissues expressing the gene, or in a tissue-specific manner, where in some tissues both alleles are active. The epigenetic imprint is passed on to daughter cells, ensuring stable inheritance of the expression pattern.

Although the exact marking mechanism is unknown, allele-specific methylation plays a central role - the inactive allele is usually methylated at CpG sites, especially in promoter regions.

In humans, about 30 genes are known to be subject to genomic imprinting.

Sources

MATOUŠ, Bohuslav, et al. Základy lékařské chemie a biochemie. 1. vydání. Praha : Galén, 2010. 540 s.