Histone methyltransferase. Preferentially dimethylates 'Lys-4' and 'Lys-27' of histone H3 forming H3K2me2 and H3K27me2. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation, while 'Lys-27' is a mark for transcriptional repression. L-lysyl(4)-[histone H3] + 2 S-adenosyl-L-methionine = 2 H(+) + N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + 2 S-adenosyl-L-homocysteine L-lysyl(27)-[histone H3] + 2 S-adenosyl-L-methionine = 2 H(+) + N(6),N(6)-dimethyl-L-lysyl(27)-[histone H3] + 2 S-adenosyl-L-homocysteine Interacts with BRD4. Highly expressed in brain, heart and skeletal muscle. Expressed at lower level in liver and lung. Defects in NSD3 may be involved in non small cell lung carcinomas (NSCLC). Amplified or overexpressed in NSCLC. A chromosomal aberration involving NSD3 is found in childhood acute myeloid leukemia. Translocation t(8;11)(p11.2;p15) with NUP98. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET2 subfamily. Contaminating sequence. Potential poly-A sequence. Truncated N-terminus.