Discovering a novel histone methyltransferase that writes a previously unknown chapter in the epigenetic code
Imagine a magnificent library containing all the instructions needed to build and maintain a living organism. This library—your genome—would be useless without a sophisticated system for organizing which books are open, which are closed, and which are bookmarked for future reference. Epigenetics, the study of heritable changes in gene function that don't involve changes to the underlying DNA sequence, represents precisely this organizational system within our cells.
At the heart of this system are histone modifications—chemical tags that serve as annotations in the margins of our genetic books, guiding cellular machinery to the right information at the right time.
Chemical modifications that regulate gene expression without altering DNA sequence.
Molecular bookmarks that guide cellular machinery to specific genomic locations.
Inside the cell nucleus, DNA doesn't float freely but is tightly wrapped around histone proteins like thread around spools. These DNA-histone complexes form nucleosomes, the fundamental units of chromatin.
Each histone protein has a tail that extends outward, serving as a platform for various chemical modifications—including methylation (adding methyl groups), acetylation (adding acetyl groups), and phosphorylation (adding phosphate groups).
| Histone Mark | Associated Function | Status Before Set7 Discovery |
|---|---|---|
| H3K4me1 | Enhancer regions, transcriptional activation | Well-established |
| H3K9me3 | Heterochromatin formation, gene silencing | Well-established |
| H3K27me3 | Developmental gene regulation | Well-established |
| H3K36me3 | Transcriptional elongation | Well-established |
| H3K37me1 | Unknown | Newly discovered with Set7 |
Before its identification as a histone methyltransferase, Set7 was simply one of many SET domain-containing proteins in the fission yeast genome with unknown function. Scientists had identified at least 13 SET-containing proteins in Schizosaccharomyces pombe, but only about half had confirmed methyltransferase activity and known substrates 1 .
The three-dimensional structure of Set7 revealed how it achieves its specificity. The enzyme contains a highly conserved SET domain common to most methyltransferases, which is responsible for catalytic function 3 .
Interestingly, Set7 exhibits different kinetic properties depending on its substrate. With free histones, it follows classic hyperbolic (Michaelis-Menten) kinetics, but with nucleosome core particles, it displays sigmoidal kinetics, suggesting allosteric regulation 3 .
Set7 forms a dimer with specific binding for H3K37
Precise binding pocket for K37 excluding K36
Sigmoidal kinetics with nucleosomal substrates
| Aspect of Gametogenesis | Normal Cells | Set7 Deletion Mutants |
|---|---|---|
| Spore number | Consistent (4 spores) | Aberrant numbers |
| Spore morphology | Normal | Aberrant |
| Gametogenesis progression | Normal | Defective |
| H3K37 methylation | Increases during gametogenesis | Absent |
Studying specialized enzymes like Set7 requires a specific set of research tools and reagents. The following toolkit has been essential for characterizing Set7's structure, function, and biological role:
H3K37 methylation represents a previously unrecognized histone mark, expanding our understanding of epigenetic regulation.
Crucial role in gametogenesis suggests importance in developmental transitions and reproductive biology 1 .
The characterization of Set7 as an H3K37 methyltransferase in fission yeast represents a beautiful example of scientific discovery—taking a protein of unknown function and revealing its specific role in the complex orchestra of epigenetic regulation. This discovery not only adds a new piece to the histone code puzzle but also opens new avenues for understanding how cells manage developmental transitions.
The epigenetic library, with its elaborate system of annotations and bookmarks, is gradually yielding its secrets. Set7 represents one newly discovered librarian in this system, specializing in a particular annotation that appears crucial during life's reproductive chapters.