Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:27571355, PubMed:22099308, PubMed:19808676, PubMed:29728617). Also monomethylates nucleosomal histone H3 at 'Lys-36' (H3K36me) in vitro (PubMed:22099308). Does not trimethylate nucleosomal histone H3 at 'Lys-36' (H3K36me3) (PubMed:22099308). However, specifically trimethylates histone H3 at 'Lys-36' (H3K36me3) at euchromatic regions in embryonic stem (ES) cells (By similarity). By methylating histone H3 at 'Lys-36', involved in the regulation of gene transcription during various biological processes (PubMed:16115125, PubMed:22099308, PubMed:29728617). In ES cells, associates with developmental transcription factors such as SALL1 and represses inappropriate gene transcription mediated by histone deacetylation (By similarity). During heart development, associates with transcription factor NKX2-5 to repress transcription of NKX2-5 target genes (By similarity). Plays an essential role in adipogenesis, by regulating expression of genes involved in pre-adipocyte differentiation (PubMed:29728617). During T-cell receptor (TCR) and CD28-mediated T-cell activation, promotes the transcription of transcription factor BCL6 which is required for follicular helper T (Tfh) cell differentiation (By similarity). During B-cell development, required for the generation of the B1 lineage (By similarity). During B2 cell activation, may contribute to the control of isotype class switch recombination (CRS), splenic germinal center formation, and the humoral immune response (By similarity). Plays a role in class switch recombination of the immunoglobulin heavy chain (IgH) locus during B-cell activation (By similarity). By regulating the methylation of histone H3 at 'Lys-36' and histone H4 at 'Lys-20' at the IgH locus, involved in TP53BP1 recruitment to the IgH switch region and promotes the transcription of IgA (By similarity). Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2). Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:22099308). Methylation of histone H3 at 'Lys-27' is controversial (PubMed:18172012, PubMed:22099308). Mono-, di- or tri-methylates histone H3 at 'Lys-27' (H3K27me, H3K27me2 and H3K27me3) (PubMed:18172012). Does not methylate histone H3 at 'Lys-27' (PubMed:22099308). May act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment (PubMed:11152655, PubMed:18172012). L-lysyl(36)-[histone H3] + S-adenosyl-L-methionine = H(+) + N(6)-methyl-L-lysyl(36)-[histone H3] + S-adenosyl-L-homocysteine L-lysyl(36)-[histone H3] + 2 S-adenosyl-L-methionine = 2 H(+) + N(6),N(6)-dimethyl-L-lysyl(36)-[histone H3] + 2 S-adenosyl-L-homocysteine Interacts with HDAC1. Interacts (via PHD-type zinc fingers 1, 2 and 3) with SALL1. Interacts (via PHD-type 1, 2 and 3) with SALL4. Interacts with NANOG. Interacts with OGT. Interacts (via HMG box) with NKX2-5. In embryonic stem (ES) cells, localizes to small foci, probably corresponding to euchromatin (By similarity). In B-cells, localizes to Ig heavy chain switch region during class switch recombination (By similarity). Widely expressed (PubMed:9618163, PubMed:18172012). Predominantly expressed in thymus and testis (PubMed:9787135, PubMed:18172012). A chromosomal aberration involving NSD2 is a cause of multiple myeloma tumors. Translocation t(4;14)(p16.3;q32.3) with IgH. NSD2 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. NSD2 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET2 subfamily. Depending on the experimental set up and substrate used, NSD2 has been shown to mono-, di- or tri-methylate 'Lys-27', 'Lys-36' or 'Lys-79' of histone H3 and 'Lys-20' or 'Lys-44' of histone H4 (PubMed:19808676). However, dimethylation of nucleosomal histone H3 at 'Lys-36' (H3K36me2) is likely to be the physiological reaction catalyzed by NSD2 (PubMed:19808676, PubMed:22099308).