To begin to answer that question Berger, Govin, and their colleagues developed a way to systematically mutate portions of two proteins, histone H3 and histone H4, looking for defects in spore formation.
DNA in a cell is not like a free-floating tangle of yarn; it is tightly wrapped around protein spindles. Those spindles are built of histone proteins, and chemical changes to these spool proteins can either loosen or tighten their interaction with DNA, affecting, among other things, gene expression. Berger and her team used their mutants more than 100 were tested -- to identify novel histone modifications key to gamete formation.
According to Berger and Govin's analysis, sites on both histone H3 and H4 turned out be important. One critical modification site the team picked up is threonine-11 on histone H3 (H3T11), the phosphorylation of which is required to complete meiosis. The researchers also found a trio of lysines on histone H4, whose acetylation enables efficient compaction of chromosomal DNA into mature spores. The team demonstrated that these modifications also occur during mouse sperm formation and identified some candidates for the proteins that both "read" and "write" those modifications, as well.
Berger said the study is noteworthy on several levels. First, it establishes a screening method to identify epigenetic changes during sperm or egg formation, a process Govin is already applying to other histone proteins. Second, it proves that yeast spore formation closely models the mechanisms of mammalian sperm formation, a key advance given the complexity of mammalian genetics and the technical hurdles inherent in running a genetic screen in mice. Finally, assuming these epigenetic marks are also present and serve similar functions in humans, the study identifies potential b
|Contact: Karen Kreeger|
University of Pennsylvania School of Medicine