| NSF Org: |
PHY Division Of Physics |
| Recipient: |
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| Initial Amendment Date: | July 18, 2017 |
| Latest Amendment Date: | July 18, 2017 |
| Award Number: | 1743900 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Krastan Blagoev
kblagoev@nsf.gov (703)292-4666 PHY Division Of Physics MPS Directorate for Mathematical and Physical Sciences |
| Start Date: | August 1, 2017 |
| End Date: | July 31, 2020 (Estimated) |
| Total Intended Award Amount: | $1,000,000.00 |
| Total Awarded Amount to Date: | $1,000,000.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
77 MASSACHUSETTS AVE CAMBRIDGE MA US 02139-4301 (617)253-1000 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
77 Massachusetts Ave Cambrdige MA US 02139-4301 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
Cellular Dynamics and Function, OFFICE OF MULTIDISCIPLINARY AC, PHYSICS OF LIVING SYSTEMS, INSPIRE |
| Primary Program Source: |
01001718DB NSF RESEARCH & RELATED ACTIVIT |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.049 |
ABSTRACT
The main goal of this RAISE Award project is to discover fundamental aspects of gene regulation in mammals. Many diseased cellular states (including cancer and autoimmunity) are associated with aberrant regulation of transcription of genes regulated by super-enhancers (SEs), large clusters of enhancers that regulate the transcription of genes important for cell type specific processes in both healthy and diseased (e.g., cancer) states.. Therefore, the proposed fundamental studies are of significance to the design of therapies for diseases that have a large toll on human health. The immediate potential impact of the studies concerns inhibitors of SEs that are currently being tested in clinical trials to treat cancer and other diseases. This effort also has an important training component. Undergraduate research is an integral part of labs at MIT. Formal mechanisms such as the MIT Undergraduate Opportunities Program (UROP), the MIT Summer Research Program and Amgen Scholars Program for underrepresented minorities, will be used to recruit undergraduates to the PI's laboratories. One PI will also participate in ACCESS, a weekend at MIT for underrepresented minority students designed to make them aware of opportunities for graduate study. The impact of this research on science and technology will be disseminated to the broader scientific community through the production of a video learning module targeted at both the broad community of citizens and specifically the K-12 educational audience. MIT has been at the epicenter of research at the convergence of the physical, life, and engineering sciences. The PIs will teach courses wherein this interdisciplinary work will be highlighted.
Super-enhancers are occupied by an unusually high density of interacting molecules, and are able to drive higher levels of transcription than typical enhancers. Several lines of evidence suggest that they form via cooperative processes, and SEs are far more vulnerable than typical enhancers to perturbation of components that are commonly associated with most enhancers. Recently, the PIs proposed that a phase separated multi-molecular assembly regulates the formation and function of SEs (Cell, 2017). They suggested that some puzzles associated with SE function are consistent with such a model. These results provide just a starting point to explore the role of phase separation in gene control in mammals. By bringing together sophisticated theoretical studies (rooted in statistical physics) and biological experiments, the PIs now aim to study their novel proposal with the goal of developing a conceptual framework for understanding gene regulation in mammals, and why SEs evolved to regulate key genes. The mechanistic insights thus gleaned will also apply to diverse processes in eukaryotic cells that are mediated by phase separated membraneless organelles. By bringing together approaches rooted in physics and biology, the PIs aim to address the following significant questions: 1] What are the fundamental physical and biological principles that determine how SEs form and function to regulate gene transcription in mammals? 2] Why have genes with the most prominent roles in cell identity evolved to be regulated by SEs? 3] Why do cancer cells have SE-regulated oncogenes, and why are these so vulnerable to drugs that inhibit certain transcriptional regulators? In order to take steps toward answering these questions, the PIs propose to study two major topics: 1] Understanding the nature of the phase transition and its implications for gene regulation. 2] Understanding how super-enhancers nucleate and form.
This RAISE project is being jointly funded by the Physics of Living Systems program in the Division of Physics in the Mathematical and Physical Sciences Directorate, by the Cellular Cluster in the Division of Molecular and Cellular Biosciences in the Biosciences Directorate, and by the Office of Integrative Activities.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Higher organisms, like humans, have many types of cells, which work together to mediate complex functions. Each cell in our body, however, has the same genetic information encoded in different genes contained in our DNA. A gene encodes information on proteins. Proteins enable a cell’s functions. Different cell types (e.g., heart cell, skin cell, etc) perform different functions because in each cell type a distinct set of proteins are expressed. That is, in each cell type some genes that encode information on proteins are allowed to be transcribed and translated into proteins, and other genes are silenced. The transcription of genes in higher organisms is regulated by parts of DNA called enhancers. The transcription of genes that are critical for defining a cell’s identity are regulated by clusters of enhancers, called super-enhancers. We showed that the formation and function of super-enhancers is mediated by the formation of liquid-like droplets comprised of the molecules necessary for transcription to occur. This is much like dewdrops forming on a blade of grass (DNA). We also described the conditions, including characteristics of the DNA sequence, that result in the formation of these liquid-like droplets at specific locations on the DNA that define enhancers. Our work involved close collaborations between physical and life scientists. Thus, the work done with support from the grant has led to the education of physicists and biologists who can work on the physics of living systems and collaborate with each other. The topic of phase separation in cell biology was also included in graduate courses. As part of our broader outreach efforts, we organized a Banbury Center conference in December 2018 that brought together the community of people working on the role of phase separation in cell biology. We also organized the annual NSF-sponsored meeting on Genome Architecture and Function in June 2020, which brought together physical and life scientists working on this topic.
Last Modified: 09/22/2020
Modified by: Arup K Chakraborty
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