News | How Do Men Keep Producing Sperm? The Answer May Lie in the Enzyme DOT1L
Male and female reproductive biology differ fundamentally: women are born with their lifetime supply of eggs, while men continuously produce new sperm throughout adulthood. This renewal depends on specialized cells called spermatogonial stem cells (SSCs). How SSCs maintain their capacity for self-renewal, however, has remained unclear.
A team at the University of Pennsylvania School of Veterinary Medicine has now published research in Genes & Development identifying DOT1L as a key stem-cell self-renewal factor. The finding may reshape research into spermatogenesis and potentially support efforts to create sperm from scratch in the laboratory.
The study was led by Jeremy Wang, Ralph L. Brinster President's Distinguished Professor at Penn Vet.
"We discovered DOT1L's role somewhat by chance," Professor Wang said. Scientists already knew that DOT1L is widely present in many cell types and can regulate gene expression. Earlier experiments showed that mouse embryos could not survive when DOT1L was absent from every cell. The team therefore deleted the gene only in mouse germ cells to examine its specific reproductive effects.
The results were unexpected. The mice appeared healthy, but after the first round of spermatogenesis, their spermatogonial stem cells were rapidly depleted and could no longer produce new sperm. Sperm development in mice lacking DOT1L showed progressive failure: first they could not produce spermatogonia, then spermatocyte numbers declined, and eventually round spermatids and mature sperm disappeared.
Further experiments confirmed the finding. When scientists switched off DOT1L in adult mice, sperm production again declined progressively. Together, the results indicate that DOT1L is essential for spermatogonial stem-cell self-renewal; without it, these stem cells cannot maintain long-term function.
DOT1L has previously been studied mainly in leukemia. It is a histone methyltransferase that regulates gene expression by adding methyl groups to histones. To test whether this mechanism also applies to spermatogenesis, Wang's team used a chemical inhibitor to block DOT1L enzymatic activity. Inhibited spermatogonial stem cells produced far fewer spermatogonia, and after transplantation into healthy mice, their stem-cell activity fell by nearly half.
The researchers further found that DOT1L may act by activating the Hoxc gene family, a group of transcription factors that regulates the expression of key genes. "We believe DOT1L enhances the expression of Hoxc transcription factors through methylation, and these factors may drive continued spermatogonial stem-cell renewal," Wang said.
He added: "Our long-term goal is to master key factors such as DOT1L so we can reprogram somatic cells and ultimately produce germ cells in culture through in vitro gametogenesis. Starting from adult cells and overcoming both spermatogonial stem-cell generation and meiosis is one of the most promising frontiers in reproductive medicine."
News | How Do Men Keep Producing Sperm? The Answer May Lie in the Enzyme DOT1L
News | How Do Men Keep Producing Sperm? The Answer May Lie in the Enzyme DOT1L
Male and female reproductive biology differ fundamentally: women are born with their lifetime supply of eggs, while men continuously produce new sperm throughout adulthood. This renewal depends on specialized cells called spermatogonial stem cells (SSCs). How SSCs maintain their capacity for self-renewal, however, has remained unclear.
A team at the University of Pennsylvania School of Veterinary Medicine has now published research in Genes & Development identifying DOT1L as a key stem-cell self-renewal factor. The finding may reshape research into spermatogenesis and potentially support efforts to create sperm from scratch in the laboratory.
The study was led by Jeremy Wang, Ralph L. Brinster President's Distinguished Professor at Penn Vet.
"We discovered DOT1L's role somewhat by chance," Professor Wang said. Scientists already knew that DOT1L is widely present in many cell types and can regulate gene expression. Earlier experiments showed that mouse embryos could not survive when DOT1L was absent from every cell. The team therefore deleted the gene only in mouse germ cells to examine its specific reproductive effects.
The results were unexpected. The mice appeared healthy, but after the first round of spermatogenesis, their spermatogonial stem cells were rapidly depleted and could no longer produce new sperm. Sperm development in mice lacking DOT1L showed progressive failure: first they could not produce spermatogonia, then spermatocyte numbers declined, and eventually round spermatids and mature sperm disappeared.
Further experiments confirmed the finding. When scientists switched off DOT1L in adult mice, sperm production again declined progressively. Together, the results indicate that DOT1L is essential for spermatogonial stem-cell self-renewal; without it, these stem cells cannot maintain long-term function.
DOT1L has previously been studied mainly in leukemia. It is a histone methyltransferase that regulates gene expression by adding methyl groups to histones. To test whether this mechanism also applies to spermatogenesis, Wang's team used a chemical inhibitor to block DOT1L enzymatic activity. Inhibited spermatogonial stem cells produced far fewer spermatogonia, and after transplantation into healthy mice, their stem-cell activity fell by nearly half.
The researchers further found that DOT1L may act by activating the Hoxc gene family, a group of transcription factors that regulates the expression of key genes. "We believe DOT1L enhances the expression of Hoxc transcription factors through methylation, and these factors may drive continued spermatogonial stem-cell renewal," Wang said.
He added: "Our long-term goal is to master key factors such as DOT1L so we can reprogram somatic cells and ultimately produce germ cells in culture through in vitro gametogenesis. Starting from adult cells and overcoming both spermatogonial stem-cell generation and meiosis is one of the most promising frontiers in reproductive medicine."
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