Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:19483677, PubMed:32862441, PubMed:31636135). Also monomethylates nucleosomal histone H3 at 'Lys-36' (H3K36me) in vitro (PubMed:19483677). Does not trimethylate nucleosomal histone H3 at 'Lys-36' (H3K36me3) (By similarity). However, specifically trimethylates histone H3 at 'Lys-36' (H3K36me3) at euchromatic regions in embryonic stem (ES) cells (PubMed:19483677). By methylating histone H3 at 'Lys-36', involved in the regulation of gene transcription during various biological processes (PubMed:19483677, PubMed:31636135, PubMed:32862441, PubMed:23241889). In ES cells, associates with developmental transcription factors such as SALL1 and represses inappropriate gene transcription mediated by histone deacetylation (PubMed:19483677). During heart development, associates with transcription factor NKX2-5 to repress transcription of NKX2-5 target genes (PubMed:19483677). Plays an essential role in adipogenesis, by regulating expression of genes involved in pre-adipocyte differentiation (By similarity). 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 (PubMed:31636135). During B-cell development, required for the generation of the B1 lineage (PubMed:32862441). During B2 cell activation, may contribute to the control of isotype class switch recombination (CRS), splenic germinal center formation, and the humoral immune response (PubMed:32862441). Plays a role in class switch recombination of the immunoglobulin heavy chain (IgH) locus during B-cell activation (PubMed:23241889). 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 (PubMed:23241889). Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (By similarity). Mono-, di- and tri-methylates histone H3 at 'Lys-27' (H3K27me, H3K27me2, H3K27me3) (PubMed:18172012). Methylation of histone H3 at 'Lys-27' is controversial (By similarity). May act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment (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 (PubMed:19483677). Interacts (via PHD-type zinc fingers 1, 2 and 3) with SALL1 (PubMed:19483677). Interacts (via PHD-type 1, 2 and 3) with SALL4 (PubMed:19483677). Interacts with NANOG (PubMed:19483677). Interacts with OGT (PubMed:19483677). Interacts (via HMG box) with NKX2-5 (PubMed:19483677). In embryonic stem (ES) cells, localizes to small foci, probably corresponding to euchromatin (PubMed:19483677). In B-cells, localizes to Ig heavy chain switch region during class switch recombination (PubMed:23241889). During B-cell development, expressed in early B2 cell progenitors (pre- and pro-B cells) with a decrease in expression at later stages. Ubiquitously expressed in early development (PubMed:9618163). Highly expressed in neuroepithelium at 10.5 dpc, and in the forebrain, midbrain, frontal facial region, jaw, heart but not in the endocardial cushion, and cartilage primordial at 14.5 dpc (PubMed:19483677). Induced in CD4(+) T-cell in response to T-cell receptor (TCR) and CD28 stimulation (at protein level) (PubMed:31636135). Induced in B2-cells by IgM antibodies or lipopolysaccharide (LPS) stimulation (PubMed:32862441). Offspring number is low at birth (PubMed:19483677). After birth, pups have growth retardation and die within 10 days (PubMed:19483677). At 15.5 dpc, levels of trimethylated 'Lys-36' on histone H3 are reduced (PubMed:19483677). At 18.5 dpc, embryos are smaller with midline fusion defects due to a lack of ossification centers and some have cleft palates (PubMed:19483677). They also have heart defects including atrial and ventricular septal defects (PubMed:19483677). Conditional knockout in CD4(+) T-cells, reduces dimethylation of histone H3 at 'Lys-36' at the Bcl6 gene locus in response to T-cell activation which results in impaired Bcl6 expresseion (PubMed:31636135). Following immunization with ovalbumin antigen or sheep red blood cells, or infection with LCMV virus, follicular helper T (Tfh) cell differentiation and germinal center B cell response are reduced (PubMed:31636135). Also, following infection with LCMV virus, clearance of the virus is delayed (PubMed:31636135). No defect in T-cell development (PubMed:31636135). 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 (By similarity). However, dimethylation of nucleosomal histone H3 at 'Lys-36' (H3K36me2) is likely to be the physiological reaction catalyzed by NSD2 (By similarity). Incorrectly indicated as originating from human.