In eukaryotic cells, transcriptional regulators must act on DNA that is packaged into chromatin. Cells can therefore regulate genes by changing how accessible a DNA region is without changing its nucleotide sequence.

Three important mechanisms are nucleosome remodeling, histone modification and DNA methylation.

Nucleosome remodeling

Energy-consuming chromatin-remodeling complexes can reposition, remove or restructure nucleosomes. Exposing a promoter or enhancer can make transcription-factor binding easier; covering the same region can make binding harder.

Histone modifications

Histone proteins can be covalently modified at particular amino-acid residues. Such modifications can change chromatin interactions or create binding sites for proteins that promote more open or more compact chromatin states.

A histone modification is therefore not a universal binary 'on' or 'off' mark. Its effect depends on the modified residue, the chemical group, neighboring modifications and the proteins that recognize the pattern.

DNA methylation

Cells can also add methyl groups ($-\mathrm{CH_3}$) to particular DNA bases. In many eukaryotic contexts, methylation of regulatory DNA is associated with reduced transcription, partly because it can alter protein binding and recruit proteins that favor repressed chromatin. The relationship is context dependent rather than an absolute rule.

What makes regulation epigenetic?

Epigenetic regulation refers to relatively stable changes in gene activity or cellular state that are maintained without changing the underlying DNA sequence. Some chromatin states can be copied through cell division because enzymes preferentially restore modifications or protein assemblies characteristic of the previous state.

Not every temporary transcription-factor binding event is epigenetic, and epigenetic does not mean irreversible. Chromatin states can change during development or in response to signals.

This creates a layered regulatory architecture:

DNA sequence
   ↓
chromatin accessibility
   ↓
transcription-factor access
   ↓
transcriptional output

Chromatin regulation therefore controls which sequence information is physically available to the transcription machinery, adding a durable but reversible regulatory layer above the DNA sequence itself.