| All DNA-templated processes are regulated by chromatin and its posttranslational modifications. One such modification, lysine methylation, has important functions in many biological processes that include heterochromatin formation, X-chromosome inactivation, and transcriptional regulation. The nuclear receptor SET domain containing (NSD) family of histone lysine methyltransferases is a critical participant in chromatin integrity as evidenced by the large number of human diseases associated with the aberrant expression of its family members. However, there has been no consensus on the specific targets of these enzymes in the literature. In my study I demonstrate that NSD2 can exhibit disparate target preferences based on the nature of the substrate provided. The NSD2 complex purified from human cells and recombinant NSD2 both exhibit specific targeting of histone H3 lysine 36 when provided with nucleosome substrates, but histone H4 lysine 44 is the primary target in the case of octamer substrates. This disparity is abolished when NSD2 is presented with octamer targets along with short single- or double-stranded DNA. In this case, the product is di-methylated H3K36, even though nucleosomes are not formed. This study clarifies in part the previous discrepancies reported with respect to NSD targets. On the basis of my finding that DNA binds directly to the SET domain of NSD2 I propose that DNA acts as an allosteric effector of NSD2 such that H3K36 becomes the preferred target. |
