Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity

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Abstract
Methylation of histone lysine residues can be reversed through the action of demethylases such as JMJD2A. Structures of JMJD2A bound to various methylated histone H3 peptides offer insight into the recognition mechanisms and specificity of histone demethylases. Post-translational histone modification has a fundamental role in chromatin biology and is proposed to constitute a ‘histone code’ in epigenetic regulation1,2. Differential methylation of histone H3 and H4 lysyl residues regulates processes including heterochromatin formation, X-chromosome inactivation, genome imprinting, DNA repair and transcriptional regulation3. The discovery of lysyl demethylases using flavin (amine oxidases)4 or Fe(ii) and 2-oxoglutarate as cofactors (2OG oxygenases)5,6,7 has changed the view of methylation as a stable epigenetic marker. However, little is known about how the demethylases are selective for particular lysyl-containing sequences in specific methylation states, a key to understanding their functions. Here we reveal how human JMJD2A (jumonji domain containing 2A), which is selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (H3K9me3/me2 and H3K36me3/me2), discriminates between methylation states and achieves sequence selectivity for H3K9. We report structures of JMJD2A–Ni(ii)–Zn(ii) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36. The structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site. We propose a mechanism for achieving methylation state selectivity involving the orientation of the substrate methyl groups towards a ferryl intermediate. The results suggest distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect the complexity of reversible histone methylation and its role in chromatin biology.