Histone substrate recognition by histone H3K36 lysine methyltransferases

Histone H3 methylation at Lys36 is widespread on chromatin and is closely related to active transcription, DNA damage and repair．H3K36 can be methylated into mono-, di- and tri-methylation states．Currently, SETD2 is the only known human methyltransferase responsible for H3K36 tri-methylation, while NSD1, NSD2, NSD3 and ASH1L are responsible for H3K36 di-methylation. H3K36 methyltransferases are very specific for substrate histones, and thus are important for the distribution and methylation status of H3K36．In addition, their aberrant expressions are closely related to human diseases．Therefore, deciphering substrate recognition and catalysis mechanisms of these H3K36 methyltransferases are important to understand the epigenetic regulation mechanisms and the physiological roles of these enzymes in vivo．Previous studies on H3K36 methyltransferases greatly facilitated the understanding of their catalytic mechanisms．However, due to limited structural data on complexes of these enzymes with their bound substrates, questions related to their histone substrate recognition remain unanswered．With recent breakthroughs in cryo-EM technology, most complex structures of these H3K36 methyltransferases with their bound nucleosomal substrates are now solved, greatly advancing the understanding of their substrate recognition and catalysis mechanisms．This review article will focus on human H3K36 methyltransferases, with a particular emphasis on the molecular mechanisms of these enzymes．