The NSD family of protein lysine methyltransferases consists of NSD1,NSD2(WHSC1/MMSET)and NSD3(WHSC1L1).The NSD methyltransferases are overexpressed,amplified or somatically mutated in multiple types of cancer,suggesting their critical role in cancer.These enzymes methylate specific lysine residues on histone tails(H3K36)and nonhistone protein substrate(RELA/p65 subunit of NF-κB).Addition to the well characterized catalytic SET domain,NSD proteins have multiple potential chromatin-binding motifs that are clinically relevant,including five PHD domains and two PWWP domains.PWWP domains have been widely accepted as a reader domain of H3K36me,which is the product of NSD methyltransferases.Of note,the second PWWP domain is closely located with the catalytic SET domain,providing an ideal case to study the cooperation mechanism between such “reader” and “writer”.Benefited from the crystal structures of the second PWWP domain of NSD3 and SET domain of NSD1,which have an overlap between their linker,we are able to build a chimeric PWWP2-SET model of the NSD family.Our crystal structure of the NSD3-PWWP2 also reveals its potential to form a domain-swapped homodimer.Overall,our study provides structural insight into the “Reader-Writer” cooperation mechanism of the NSD family methyltransferases.