Lifelong sperm production possible

According to research conducted at the University of Pennsylvania, the DOT1L enzyme, a stem cell self-renewal factor, is required for continued sperm production in mice throughout adulthood

In contrast to women who are born with all their eggs, men may continue to produce sperm into adulthood, for which they must continually renew sperm-producing spermatogonial stem cells

This stem cell renewal relies on a recently discovered stem cell self-renewal factor called DOT1L, according to research by Jeremy Wang and colleagues at Penn's School of Veterinary Medicine

The discovery, published in the journal Genes and Development, adds another entity to the few stem cell regeneration factors that scientists have discovered

"This new factor can only be identified by the discovery of this unusual phenotype: the fact that mice lacking DOT1L cannot go on to produce sperm, identifying this key factor not only helps us understand the biology of adult germline stem cells properties, but also allow us to one day reprogram somatic cells, such as a type of skin cell called a fibroblast, into a germ cell stem cell, essentially creating gametes in a petri dish

The role of DOT1L in stem cell self-renewal was discovered by chance

"When we did this, the animals survived and looked healthy, however, when we looked closely, we found that mice with mutant DOT1L in their germ cells could complete the first round of sperm production, but then the stem cells were depleted , the mice lost all germ cells

Decreased sperm production can be caused by other problems

In further experiments, the researchers looked at DOT1L being inactivated in germ cells, not from birth but during adulthood

Other scientific groups have previously studied DOT1L in the context of leukemia

To see if the same mechanism is responsible for the results Wang and his team observed in sperm development, the researchers treated spermatogonial stem cells with a chemical that blocks the activity of DOT1L methyltransferase

The team found that DOT1L appears to regulate a family of genes called Hoxc, transcription factors that play an important role in regulating the expression of a large number of other genes

"We think DOT1L promotes the expression of these Hoxc genes through methylation," Wang said.

A long-term goal is to use DOT1L and other factors involved in reproductive stem cell self-renewal to help people with reproductive difficulties

This is the future of this field: gamete formation in vitro, recoding somatic cells into spermatogonial stem cells is one of the steps

Reference: "Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells" by Huijuan Lin, Keren Cheng, Hiroshi Kubota, Yemin Lan, Simone S.
Riedel, Kazue Kakiuchi, Kotaro Sasaki, Kathrin M.
Bernt, Marisa S.
Bartolomei, Mengcheng Luo and P.
Jeremy Wang, 23 June 2022, Genes & Development.