Coordinated methyl-lysine erasure: structural and functional linkage of a Jumonji demethylase domain and a reader domain

Both components of chromatin (DNA and histones) are subjected to dynamic postsynthetic covalent modifications. Dynamic histone lysine methylation involves the activities of modifying enzymes (writers), enzymes removing modifications (erasers), and readers of the epigenetic code. Known histone lysine demethylases include flavin-dependent monoamine oxidase lysine-specific demethylase 1 and α-ketoglutarate–Fe(II)-dependent dioxygenases containing Jumonji domains. Importantly, the Jumonji domain often associates with at least one additional recognizable domain (reader) within the same polypeptide that detects the methylation status of histones and/or DNA. Here, we summarize recent developments in characterizing structural and functional properties of various histone lysine demethylases, with emphasis on a mechanism of crosstalk between a Jumonji domain and its associated reader module(s). We further discuss the role of recently identified Tet1 enzyme in oxidizing 5-methylcytosine to 5-hydroxymethylcytosine in DNA.

► JMJD2A binds H3K4me3 or H4K20me3 and demethylates H3K9me3 or H3K36me3. ► PHF8 and KIAA1718 bind H3K4me3 and demethylate H3K9me2 or H3K27me2. ► PHF2: activation by phosphorylation. ► JARID binds DNA, H3K9me3, and demethylates H3K4me3. ► JHDM1 binds CpG DNA and demethylates H3K36me2. ► Tet1 contains an insertion with sequence similarity with the CTD of RNA polymerase II.