Scientists have discovered how a key enzyme, KDM4 B, helps protect DNA during the formation of sex cells in mice. This breakthrough could one day explain some causes of infertility and certain cancers.
DNA strands wrap around small proteins called histones. This wrapping can “turn off” parts of genes or shield them from damage. The new study shows how KDM4 B “reads” one chemical mark on a histone and then removes another nearby mark. This process happens during the creation of sperm and egg cells, known as meiosis.
The research was a joint effort between Johns Hopkins University School of Medicine, Rice University, and the University of Wisconsin-Madison. Their findings were published in the journal Nature Communications on November 14.
Understanding the Role of Histones and Epigenetic Marks
Sean Taverna, Ph.D., an associate professor at Johns Hopkins, explains that DNA alone does not tell the full story of how proteins are made in cells. Genes are like sentences in a book, but not all sentences are read every time. Histones act like tape sealing certain pages, preventing some genes from being read. This is an example of epigenetic control, where gene activity changes without altering the underlying DNA sequence.
Histones carry chemical tags, mainly methyl groups, that regulate whether genes are active or silent. Previously, Taverna’s lab studied a single-celled organism called Tetrahymena thermophila, which has two nuclei: one active and one mostly silent. They found a special histone mark, called H3K23me3, which appears in the silent nucleus during early meiosis. This mark protects parts of the genome from being cut by enzymes, which is important because DNA breaks are common during meiosis for genetic mixing.
Discovering How KDM4 Enzymes Work
At the University of Wisconsin-Madison, John Denu, Ph.D., and his team developed methods to see which proteins attach to specific histone marks. They identified three related enzymes—KDM4A, KDM4B, and KDM4C—that interact differently with histone marks. Notably, KDM4B binds only to the H3K23me3 mark.
Rice University researchers, led by George Phillips, Ph.D., then studied the 3-D structures of these enzymes. They discovered why each enzyme prefers different histone tags by altering KDM4A to behave like KDM4 B, revealing the basis for their binding preferences.
What KDM4 B Does During Meiosis
Further tests showed that after KDM4 B recognizes the H3K23me3 mark, it removes methyl groups from a nearby site, H3K36me3. This dual action—reading one mark and erasing another—is rare. Scientists believe this helps “seal off” and protect DNA regions during meiosis, preventing damage.
Taverna points out that without H3K23me3, cells like Tetrahymena struggle to reproduce because DNA damage occurs in vulnerable genome regions. This suggests that the mark and KDM4 B are crucial for healthy reproduction.
Implications for Mammalian Fertility and Disease
To explore the role in mammals, Taverna’s team examined mice and found that both H3K23me3 and KDM4B increase in immature sperm during early meiosis. They could not study eggs since meiosis in females happens before birth.
While there is no direct proof yet that problems with KDM4B or H3K23me3 cause infertility in mammals, the evidence points strongly in that direction. Researchers plan to continue investigating to better understand how this epigenetic mechanism might affect human fertility and disease development.
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