Structural insights into the regulation and the recognition of histone marks by the SET domain of NSD1

► NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 are histone methyltransferases linked to numerous cancers. ► Little is known about the NSD pathways and HMTase inhibitors are sorely needed in the epigenetic therapy of cancers. ► We investigate the regulation and the recognition of histone marks by the SET domain of NSD1. ► A unique and key mechanism is driven by a loop at the interface of the SET and postSET region. ► Implications for developing specific and selective HMTase inhibitors are presented.