Research in biology is driven by the constant tension between what we know (much) and what we don’t (much more). Take the question of the transcription of messenger RNA in the cell nucleus. Rob Singer of the Albert Einstein College of Medicine in the Bronx, NY, who has pioneered new microscopy techniques for live imaging of single mRNA molecules, would really like to know if position matters for a gene to be activated.
“This is a complicated and controversial field at the moment,” Singer says. “Probably half the people in the field believe that in the larger context of nuclear organization where genes are positioned is not important. The other half believes that it is important.” The current evidence is unclear, he says. Studies in mammalian cells describe activated genes moving to the interior for mRNA transcription while work in yeast has shown the opposite. “Right now there’s a debate about cause and effect and whether we’re looking at something that’s important for gene activation or whether it’s some downstream event that occurs after activation.”
But Singer believes the field is reaching critical mass. New technologies such as CRISPR/Cas9 plus new resources such as the NIH Common Fund’s 4D Nucleosome program, an 80+ investigator collaboration to understand nuclear organization in space and time, are moving the field toward answers. Says Singer, “There’s going to be a lot of information coming out about a variety of organisms—Drosophila, yeast, and mammals—in the next year or two.”
Debate and new data are what research meetings are all about and Singer is looking forward to ASCB 2016 in San Francisco on Wednesday, December 7, where he will be speaking at the “Nuclear Organization” symposium. Attendees, Singer predicts, “are going to hear mainly about new techniques to investigate nuclear dynamics in ways we haven’t been able to before. They will allow us to follow events in real time in the nucleus, either looking at the big picture by imaging the movement of chromosomes and chromatin or by looking at specific genes and where in the nucleus they get expressed and how they might be regulated.”
Also speaking at the symposium will be Susan M. Gasser, who is at the Friedrich Miescher Institute for Biomedical Research and University of Basel, Switzerland. Singer describes Gasser as “someone who has been involved in nuclear organization since Day One in yeast.” Her talk will be on the role of heterochromatin in a complex organism and how it stabilizes the genome, which Singer says is the Big Picture view of nuclear organization versus his single-molecule approach.
Understanding chromatin and how promoters and enhancers interact with each other through DNA loops is probably going to be a major part of any solution to the nuclear organization problem, says Singer. “I think the meat of this will be in the fine details of how DNA loops and activates sequences hundreds of kilobases away.”
But the role of genes tagged to the inner layer of the nuclear envelope or near to nuclear pore complexes is still to be figured out. “Whether that plays a role in physiology of the gene is unclear. Genes can be untagged from this location and they still work fine. Our viewpoint is that things can still work in the absence of the normal nuclear organization but we don’t know what we might have lost in its regulation.” Singer says.
“Our basic message is that everything in the cell is coordinated. The nucleus and the cytoplasm are integrated in their functions. Events in the cytoplasm feed back to the nucleus and the nucleus doesn’t know which genes to express without some feedback as to what’s going on out there in the cytoplasm. We know this intuitively but there still isn’t a good mechanism to explain how this all works together.”
Which brings Singer back to the symposium on nuclear organization at ASCB 2016. “[There is] so much more to be found that will be revealed by new technologies,” he says.