| NSF Org: |
CCF Division of Computing and Communication Foundations |
| Recipient: |
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| Initial Amendment Date: | September 7, 2016 |
| Latest Amendment Date: | September 7, 2016 |
| Award Number: | 1656201 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Phillip Regalia
pregalia@nsf.gov (703)292-2981 CCF Division of Computing and Communication Foundations CSE Directorate for Computer and Information Science and Engineering |
| Start Date: | September 1, 2016 |
| End Date: | August 31, 2018 (Estimated) |
| Total Intended Award Amount: | $200,772.00 |
| Total Awarded Amount to Date: | $200,772.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
3400 N CHARLES ST BALTIMORE MD US 21218-2608 (443)997-1898 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
3400 N. Charles Street Baltimore MD US 21218-2608 |
| 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): | Comm & Information Foundations |
| Primary Program Source: |
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| 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): | 47.070 |
ABSTRACT
Cells use an elaborate system to determine when and where specific genes will be expressed during development and differentiation as well as in response to environmental conditions and stimuli. This system is overlaid on the DNA in the form of heritable epigenetic marks that control gene expression by modifying the structural organization of the genome without changing the DNA sequence. Epigenetic marks can silence genes or activate them by adapting chromatin (a DNA/protein complex which forms chromosomes within the nucleus of eukaryotic cells) to distinct states that repress or stimulate gene activity and this can drive genetically identical cells to behave differently from each other. There is now ample evidence that aberrant epigenetic regulation can lead to disease. However, and in sharp contrast to gene mutations, epigenetic alterations can be reversed. It is therefore believed that research in understanding the human epigenome can lead to novel and highly effective therapeutic strategies for many human diseases, such as cancer, diabetes, and Alzheimer?s. A formal pursuit of the proposed research will provide a solid foundation for developing fundamentally different methods for the modeling, quantification, and analysis of epigenetic information, as compared to rather crude mathematical and computational methods currently used in the literature. This could potentially have a major impact on the area of epigenetic science, as well as on medicine and society at large, which could lead to new biological discoveries towards understanding the role of epigenetics in development, disease and aging.
The main goal of this research is to develop a novel approach for understanding the informational structure and properties of the human epigenome by using well-grounded biological assumptions and principles of statistical physics and information theory. The investigators will develop methods for quantifying epigenetic stochasticity, as well as discern and analyze epigenetic discordance between biological samples, providing new and exciting ways for studying the role of epigenetic regulation in disease and aging. By viewing the process of transmitting epigenetic information during cell division as a communication system, the concept of a methylation channel is introduced, which can be characterized by its capacity, dissipated energy, and input/output entropy. Preliminary results using real epigenetic data have demonstrated an intriguing connection between chromatin organization and informational properties of methylation channels. This shows that a merger of epigenetic biology, statistical physics and information theory may lead to fundamental insights into the relationship between the informational properties of the epigenome and nuclear organization in normal development and disease. Successful completion of the proposed work will transform the way epigenetic information is modeled, quantified, and analyzed, and lead to powerful methodologies for understanding the information theoretic content of the human epigenome and its role in development, disease, and aging.
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.
The main objective of this work was to employ well-grounded biological assumptions and principles of statistical physics and information theory in order to develop a novel approach for understanding the informational structure and properties of the human epigenome, which controls and regulates chromatin structure and gene function in human cells. This work provided a rigorous quantification of epigenetic stochasticity in cells and produced novel methods for discerning and analyzing epigenetic discordance between biological samples, and resulted in new and exciting ways for studying the role of epigenetic regulation in development, disease and aging. The merger of epigenetic biology, statistical physics, and information theory yielded many fundamental insights into the relationship between information-theoretic properties of the epigenome and nuclear organization in normal development and disease. Moreover, it provided novel methods for evaluating the informational properties of individual samples and their chromatin structure and for quantifying differences between tissue lineages, aging, and cancer at high resolution and genome-wide. The developed methodologies were successfully used to analyze DNA methylation data obtained from NASA's Twin Study, a multidisiplinary/muti-institutional study whose objective was to better understand the impact of spaceflight on the human body and to prepare for future exploration-class missions. They also successfully provided the first comprehensive analysis of DNA methylation in acute lymphoblastic leukemia (ALL), a devastating childhood disease, encapsulating the intrinsic variability of the epigenome, of central importance to tumor plasticity.
Last Modified: 09/26/2018
Modified by: John Goutsias
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