The nucleosome is the fundamental building block of the eukaryotic genome, composed of an ∼147 base-pair DNA fragment wrapping around an octameric histone protein core. DNA and histone proteins are targets of enzymatic chemical modifications that serve as signals for gene regulation. These modifications are often referred to as epigenetic modifications that govern gene activities without altering the DNA sequence. Although the term epigenetics initially required inheritability, it now frequently includes noninherited histone modifications associated with gene regulation. Important epigenetic modifications for healthy cell growth and proliferation include DNA methylation, histone acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation (SUMO = Small Ubiquitin-like Modifier). Our research focuses on the biophysical roles of these modifications in altering the structure and structural dynamics of the nucleosome and their implications in gene regulation mechanisms. As the changes are subtle and complex, we employ various single-molecule fluorescence approaches for their investigations. Our investigations revealed that these modifications induce changes in the structure and structural dynamics of the nucleosome and their thermodynamic and kinetic stabilities. We also suggested the implications of these changes in gene regulation mechanisms that are the foci of our current and future research.