SETD2(SET domain containing 2), also known as KMT3A, HYBP, HIF-1 is a ubiquitously expressed nuclear protein methyltransferase that is responsible for the majority of tri-methylation of histone H3 on lysine 36 (H3K36Me3) and methylation of this residue is associated with active chromatin. SETD2 also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. SETD2 is critical for proper regulation of transcription elongation, RNA splicing and DNA mismatch repair. Upon hyper-phosphorylation of the RNAPII CTD during activation of transcriptional elongation, SETD2 is recruited and facilitates tri-methylation of histone H3 lysine 36 in the body of transcriptionally active genes. SETD2 probably plays a role in chromatin structure modulation during elongation via its interaction with hyperphosphorylated POLR2A.