Epigenetic moonlighting: Catalytic-independent functions of histone modifiers in regulating transcription

The past three decades have yielded a wealth of information regarding the chromatin regulatory mechanisms that control transcription. The “histone code” hypothesis—which posits that distinct combinations of posttranslational histone modifications are “read” by downstream effector proteins to regulate gene expression—has guided chromatin research to uncover fundamental mechanisms relevant to many aspects of biology. However, recent molecular and genetic studies revealed that the function of many histone-modifying enzymes extends independently and beyond their catalytic activities. In this review, we highlight original and recent advances in the understanding of noncatalytic functions of histone modifiers. Many of the histone modifications deposited by these enzymes—previously considered to be required for transcriptional activation—have been demonstrated to be dispensable for gene expression in living organisms. This perspective aims to prompt further examination of these enigmatic chromatin modifications by inspiring studies to define the noncatalytic “epigenetic moonlighting” functions of chromatin-modifying enzymes.