The transfer of genomic DNA from one generation to the next is the foundation of heredity. However, observations made in a wide range of organisms over many years reveal that phenotypic information *not* encoded in DNA can also be inherited across multiple generations. For example, recent work shows that environmental factors such as diet-induced obesity [1] [2], drug exposure [3], and psychological stressors like war experiences and trauma [4], [5] can cause changes in physical traits not only in the individuals directly affected but also in their offspring. Unlike genetic inheritance, however, the mechanisms underlying this so-called trans-generational epigenetic inheritance (TEI) remain poorly understood. We and others have shown that enzymes in the lysine methyltransferase family (KMTs) play significant roles in TEI, though the nature of that role has not been resolved [6]. To address this issue, we examined the biochemical function of the SET9 and SET26 KMTs, close paralogues that we have shown to play an important role in TEI in the nematode worm Caenorhabditis elegans, using solution state NMR. We show here that SET9 is able to bind the N-terminal tail of histone H3 – and further that it displays significant selectivity for the H3 tail when the latter is post-translationally modified by trimethylation of Lys4 (H3K4me3). The H3K4me3 modification is found in nucleosomes positioned at active genes, indicating that SET9 regulates the expression of these genes. Indeed, genetic knockout data show that loss of SET9 and its close paralogue SET26 prevents the ‘spreading’ of H3K4 trimethylation, thereby limiting the expression of such genes [7]. With these data in hand, we can go on to dissect the function of the SET domain of these proteins, to address the mechanism by which they alter target gene expression and thereby shed light on the role of these proteins in TEI.