SETD8 also known as Pr-Set7, SET8, KMT5A is a nucleosome-specific monomethylase that specifically methylates H4 at Lys 20, a mark of constitutive and facultative heterochromatin. SETD8 plays a crucial role in regulating chromatin structure and gene expression through nucleosome-specific monomethylase function. SETD8 specifically methylates histone H4 at lysine 20, a modification essential for establishing and maintaining constitutive and facultative heterochromatin. This methylation mark remains stable and persists even without SETD8, highlighting importance in long-term gene regulation. SETD8 functions as a single subunit that preferentially acts on nucleosomal substrates, influencing cell-cycle-dependent transcriptional silencing and mitotic regulation in metazoans.