Researchers identified a molecule that inhibits a protein essential for sperm production thus holding promises for the development of a male contraceptive.
The total DNA contained in a human cell is about 2 meters long. The diameter of a cell nucleus is approximatively 6µm. How is it possible that such a tiny space can hold a molecule of such a length? That’s because DNA is not just floating naked in the nucleus. DNA forms with proteins a complex termed chromatin. DNA is tightly wrapped around proteins called histones, which allow the DNA to be compacted so small that it fits into the volume of the nucleus. Sperm cells have only half of the DNA quantity other cells of the body possess but this DNA has to fit in a nucleus whose volume is 10% smaller. Consequently, during sperm formation, chromatin is remodelled so that it achieves the level of condensation necessary to fit inside a sperm cell nucleus. Among other rearrangements, histones are replaced by another type of proteins called protamines as it’s impossible to compact the DNA sufficiently for the sperm nucleus using histones.
BRDT is one of the proteins involved in this remodelling process, which is essential for sperm production. We know this because the sperm chromatin of mice mutant for BRDT is not properly packaged and this defect has dramatic consequences as the male mutant mice are sterile. The structure of the BRDT protein has a pocket that recognizes and binds histones. Researchers identified a molecule named JQ1 that perfectly fits into that pocket and prevents BRDT from binding histones.
When JQ1 is administered to male mice, their testis shrink, the number of sperm they produce drops and their sperm have motility problems. In effect, these male are sterile. But once the treatment with JQ1 is stopped, testis size, sperm number and motility come back to usual and the mice are able to father children that appear completely normal.
It’ll be some time before the results recently reported in mice can be applied to humans and even more time of clinical trials before JQ1 can find its way to the market as a contraceptive for men. But we’re one step closer.
Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE (2012). Small-Molecule Inhibition of BRDT for Male Contraception. Cell, 150 (4), 673-684 DOI: 10.1016/j.cell.2012.06.045