Reprogramming sperm DNA
When a sperm and an egg combine, the genetic material from two parents merges. But the DNA in the two is initially in completely different states and it needs to be reset to make the two sets of chromosomes compatible so that cell division can occur. Factors contributed to this process by the egg are reasonably well known but nothing is understood about the paternal contribution. Now, working with Drosophila, Mia Levine has discovered a gene called HP1E which is active only during sperm development but seems to alter sperm DNA in a fashion that's crucial for subsequent successful cell division.
Mia - During the process of sperm development, the nuclear volume decreases over two hundred fold. The DNA takes on a highly compact form to fit into that tiny sperm head. And so, if you don't have the proteins that mom produces to transform dad's DNA into a usable form, effectively you get inside the egg a bright dot which represents a highly compact form of dad's DNA that simply can't participate in the later cell divisions.
Chris - And this is because, obviously, when you want mitosis, a cell to start dividing symmetrically to make two daughter cells that are genetically identical to each other, you've got to have recognition of which chromosome goes with which from each parent in order for that process to happen properly. And if the DNAs are in incompatible formats, then they're not going to partition properly, are they?
Mia - That's exactly correct. And so, dad's DNA gets dumped into the sperm in a very different confirmation than what mom's DNA looks like during that fertilization event, until they independently have to reorganize to come together into similar confirmations before that division can happen.
Chris - So, how do you dissect away what the contribution of the sperm might be to getting that DNA into the right format from what the maternal egg processes are doing?
Mia - We discovered a gene which we called HP1E, which is exclusively expressed in testes. And so by depleting this protein during sperm development and letting dad's sperm actually fertilize the egg, we're able to actually remove the contribution of that protein.
Chris - And what's the consequence?
Mia - The sperm enters the egg. The first defect that we see is during the process of condensation. And we see that dad's DNA fails to go through this condensation process. So, effectively, mom's DNA is continuing through its typical series of events but dad's DNA can't seem to "catch up".
Chris - How does the sperm do that? Does it bring that protein that was on during spermatogenesis in with the sperm or is the gene just very active in the sperm from the get go in the egg and that provides the protein.
Mia - Right. So, that was the particularly interesting piece of the story. There is another protein known in drosophila called, KD1, which actually travels with the sperm DNA into the embryo and putatively carries out its function in the egg. HP1E, instead, seems to be active exclusively during sperm development, is then lost from the DNA. And the DNA itself seems to be flagged or there's some kind of modification of which we have yet to identify that affects its function in the egg. So, we both saw the disappearance of HP1E during sperm development which supports its lack of role during DNA remodeling in the egg. And we also induced mom to make HP1E, which she usually does not, and have her dump HP1E into the egg. And we found that even when HP1E was present in the egg through mom, we were unable to rescue normal divisions. These data, in combination, support the idea that HP1E acts exclusively in dad during sperm development but not during the time when we actually see the defect occur in the egg.
Chris - Have you any idea at all what the identity of that manipulation of the sperm DNA must be in order to put it into that resistant state that you then can't get it back?
Mia - At this point, we can only speculate. There has been a surge of research done in the past decade or two to look at what else sperm is carrying besides dad's DNA that is inherited into the egg. And we know now that dad also deposits some small RNAs - messenger RNAs - into the egg. And so, the jury is out as to what HP1E does to the sperm DNA to modify it in such a way that allows it participate in nuclear divisions. However, my lab at the University of Pennsylvania will be actively investigating this question.