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Andrei Kuzmichev led a 2002 study identifying histone methyltransferase activity in a human protein complex containing Enhancer of Zeste. Biochemical isolation linked the complex to methylation of histone H3, with activity depending on an intact SET domain.^[ref]

The contribution connected a regulator of gene expression to a specific chemical activity on chromatin. Measuring a histone methylation reaction and disrupting a required domain supplied more mechanistic information than observing that two proteins occur in the same cell.

A SET domain is a protein domain found in many methyltransferases that modify lysine residues in histones and other proteins. It contributes to the catalytic machinery that transfers a methyl group to a selected target. The domain's presence suggests a family relationship, but does not by itself specify which residue a particular enzyme modifies.

In 2000, experiments on SUV39H1 and related proteins identified histone H3 lysine 9 methylation activity. Mutational and biochemical analysis localized the catalytic requirement to the SET domain together with adjacent cysteine-rich regions.^[ref] This linked a recognizable sequence region to a concrete chemical reaction on chromatin, while also showing why isolating a domain name from its surrounding structure can oversimplify enzyme function.

S. Rea is the first author of a 2000 study identifying SUV39H1 and its mouse counterpart as histone methyltransferases with a specific target: lysine 9 near the beginning of histone H3. In experiments outside living biological cells, these enzymes transferred methyl groups to that position. Mapping the catalytic activity implicated the SET domain together with neighboring regions rich in cysteine.^[ref]

The specificity is the important idea: a histone modification has an address within a protein, rather than simply changing the bulk composition of chromatin. The study also found that modification of lysine 9 interfered with phosphorylation of neighboring serine 10, illustrating how nearby chemical changes can interact. Experiments that altered the enzymes' activity in biological cells also changed histone H3 phosphorylation and produced abnormal divisions. These observations helped connect a defined catalytic reaction with the regulation of chromatin; they did not imply that every modified histone has the same effect in every biological context.^[ref]

SUV39H1 is a human histone methyltransferase that modifies lysine 9 in the amino-terminal region of histone H3. Its catalytic machinery includes a SET domain and adjoining cysteine-rich regions. The corresponding gene encodes an enzyme acting on a protein component of chromatin.^[ref]

The original biochemical work established site specificity using histone H3 substrates and mapped the catalytic requirement to regions of SUV39H1. It also found that lysine 9 methylation interfered with phosphorylation of neighbouring serine 10. This gives an illuminating example of interacting histone modifications: changing one residue can affect a modification at the next residue, so the histone tail is a chemically coupled substrate.^[ref]

For an enzyme assay, the informative measurement is formation of the specified methylated histone product. Simply detecting SUV39H1 expression establishes the presence of its protein, while activity additionally depends on the reaction conditions and available substrate.