Reflecting on a Super-Productive Summer with the 'Chromatin Consortium'
Talk about the Woods Hole magic! When four principal investigators joined forces at the Marine Biological Laboratory (MBL) last summer, they hoped to make headway on a gnarly question in cell biology. But one wildly successful experiment after another wasn’t in the cards – until it happened.
“You don’t often make a series of observations in a quick period that aren’t just one-off, neat observations, but where each one opens up a real research project that can take us over the next year,” said Michael Rosen of UT Southwestern Medical School, a principal investigator (PI) in the multi-lab collaboration.
“It’s been very, very exciting," Rosen said. “After just a few weeks here, we’re coming away with half a dozen new research programs."
Unpacking a nuclear mystery
The group credits their rapid success to meticulous preparation and their diverse and synergistic expertise, including with students and post-docs they brought to the collaboration.
“We took a long time to prepare beforehand, created sophisticated reagents and a modeling framework, so here we can develop ideas, implement experiments, and see results on a super-fast time scale,” said PI Daniel Gerlich of the Institute of Molecular Biology, Austria.
“The work we are doing is truly multidisciplinary, so being together at MBL has helped enormously in just finding the language we need to communicate, to understand how we each are looking at the problem,” said PI Rosana Collepardo-Guevara of University of Cambridge.
The group is tackling a basic inscrutability packed in the nucleus of our cells, where the genome is stored in chromosomes. Chromosomes are made of chromatin – extremely long strands of DNA wrapped around protein molecules.
“If you took all the DNA in a human body and lined it up end to end, it would go from the Earth to Pluto and back,” said Rosen. “It strings all the way out to the end of our solar system, but it has to fit into your body.”
Chromatin is highly folded and locally compacted to a variable degree, to regulate gene expression.
“Chromatin regions are more compact or less compact, based on usage,” said Sy Redding of University of Massachusetts Chan Medical School, the group’s fourth PI. “For example, you don’t need fingernails in your liver, right?” Right, so in liver cells, the fingernail-making stretch of the genome remains inactive.
The big question then, is, what “opens up” a stretch of chromatin, makes it accessible to the cell for gene activation? Many labs and biotech companies are asking this very thing.
“If we can understand how chromatin organization controls gene activation -- which is necessary for all of biology -- we can understand what happens when it goes awry, causing changes in the genome and therefore disease,” Rosen said.
Phase separation and chromatin
The group is betting that chromatin compaction is governed by liquid-liquid phase separation (LLPS), a biophysical process akin to oil separating from water. (See their 2019 paper, which Collepardo-Guevara called “transformative in the field of chromatin research.”)
“If chromatin were to compact into a solid, it couldn’t function in the cell,” said Rosen. “Its molecules need to be able to move.” That dynamism is offered by LLPS, where molecules condense into membrane-free liquid droplets, as needed by the cell.
“Biology uses LLPS to concentrate molecules in general, but in this case, we think, to compact chromatin while allowing it to still maintain function,” Rosen said. The group is bearing down on two big questions: How does LLPS dynamically “compartmentalize” chromatin, and what are the functions of this compartmentalization?
“We’re coming at this from very different starting points,” cell biologist Gerlich said. “In my lab, we look in cells, where things are complex and hard to understand. Mike Rosen and Sy Redding are biochemists – they take the cellular components, purify them, study them in vitro, and characterize them with sophisticated techniques under very defined conditions.” Collepardo-Guevara, a computational biophysicist, develops theoretical models at many scales, ranging from single atoms up to collections of molecules condensing, to try and recapitulate the mechanistic forces taking place. “Because we have different areas of expertise, we can cover all these scales,” Rosen said.
“At large scale, the chromatin inside a nucleus is not a liquid,” Gerlich said. “Chromatin fibers themselves have very constrained mobility because the material, like the long stretches of DNA, is very viscous. One of our goals is to understand how, at a local scale, you have mobility in a liquid-like state and how that translates to long-range structural organization.”
What’s the recipe for early discovery?
The MBL has been home turf for scientists studying LLPS since the phenomenon was first observed in the 2008 MBL Physiology course. Immediately recognized as a new way for cells to organize internally, the study of LLPS (a process that can generate certain biomolecular condensates, or cellular compartments that form without a surrounding membrane) opened a floodgate of discovery. Evidence has mounted that condensates regulate critical cellular processes, from cell division to gene expression, and are involved in the development of cancer, neurodegenerative disease, and many other disorders. (Here’s a timeline of pioneering research on LLPS at the MBL.)
In 2013, with support from the Howard Hughes Medical Institute, Rosen, Ron Vale, and Jim Wilhelm founded the MBL-HHMI Summer Institute, which convened more than 70 scientists from around the world at MBL over five consecutive summers. Their goal was generating knowledge in the just-emerging field of biomolecular condensates. The Summer Institute was fantastically productive, resulting in at least 25 published papers and quantum leaps in understanding how condensates form and behave in the cell.
The success of the Summer Institute was on Rosen’s mind as last summer’s collaboration, which they call “The Chromatin Consortium,” took shape.
“These programs focus on the initial discovery part of science, the spark of creativity that will eventually lead to a project that a granting agency will fund,” Rosen said. “It’s very hard to find funding to gather people to allow that initial spark to happen. But being back at MBL again, feeling the excitement and seeing the pace of discovery, makes me think we, as a scientific community, need to find ways of enabling this. It takes the science up another click and allows the next set of questions to be addressed.”
Gerlich noted how powerful this model is for students and post-docs in the consortium, too. “It’s an informal, discovery-based way of training, but they see how different PIs interact, how you can do experiments at a fast pace. It’s really changed my home lab a lot. The students return and spread the word, and it radiates.”
The scientists hope more mechanisms will emerge to support this kind of multidisciplinary, early-phase discovery research.
“It’s an incredibly productive and powerful way to do science,” Rosen said.
The Chromatin Consortium was supported in part this year by Daniel and David Isenberg of Woods Hole to promote collaboration and honor the work of their father, Irv Isenberg, who was an MBL scientist and a pioneer in histone research. The Isenbergs funded meals and joint housing in the “Chromatin Cottage” for some of the students in the Consortium, furthering collaboration and community.