Engineering biology through DNA’s environment


Credit: Ralph Mazitschek, Mass General Hospital/Harvard University; Emilia Entcheva and Alejandro Villagra, George Washington University

To advance the engineering of biology at the molecular and cellular levels, the National Science Foundation (NSF) has awarded $16 million for research to characterize the regulation of gene activity and expression, and to create strategies to modify those processes without altering the DNA sequence.

Chromatin — a combination of DNA, RNA and proteins within a cell's nucleus — can be modified by attaching additional molecules. This can cause altered gene expression without actually changing the cell's DNA. These so-called epigenetic changes can alter an organism's traits, or phenotype, and may even be passed to offspring.

NSF-funded researchers will create tools for studying, manipulating and modeling how epigenetic mechanisms affect gene expression and ultimately the characteristics and functions of organisms. Research projects will develop new models that describe chromatin, which will allow researchers to understand how nanoscale changes within cells result in altered gene expression.

"Precise regulation of cells, thanks to a combination of advanced techniques from engineering and biology, may allow us to combat disease, engineer crop improvements, and design organisms that can remediate environmental problems or adapt to environmental change," said Dawn Tilbury, NSF assistant director for Engineering.

Supported by the NSF Directorate for Engineering's Emerging Frontiers in Research and Innovation (EFRI) program, and co-funded by the Biological Sciences Directorate and Mathematical and Physical Sciences Directorate, the awards signal a major investment in engineering biology and align with one of NSF's 10 Big Ideas for long-term discovery and innovation, Understanding the Rules of Life: Predicting Phenotype.

Established in 2007, EFRI seeks to inspire and enable researchers to expand the limits of knowledge in the service of grand engineering challenges and national needs.

"High-resolution imaging — down to the nanoscale — promises new insights into systems within the cell nucleus, as well as changes with age, disease or other conditions," said Leon Esterowitz, lead NSF EFRI program director. "Fundamental understanding of the role of the chromatin nanoenvironment in DNA expression will enable many new medical treatments in the future, as well as providing a potential path to the development of bio-based processes and manufacturing."

"Applying innovative strategies and cutting-edge methods for engineering chromatin will also reveal key principles linking chromatin-level organization of the genome to its functional output," said Karen Cone, Biological Sciences program director and EFRI team member. "These discoveries will be vital in solving the long-standing question of how an organism's characteristic phenotype is shaped by interactions of the dynamic epi-genome and the environment."

The NSF EFRI Chromatin and Epigenetic Engineering (CEE) investment will support potentially transformative research by eight interdisciplinary teams:

  • Ascribing function to chromatin with coordinated live-cell epigenomic sensors and scalpels, Albert Keung, North Carolina State University, with Caroline Laplante and Balaji Rao
  • Engineering technologies to determine causal relationships between chromatin structure and gene regulation, Charles Gersbach, Duke University, with Brenton Hoffman, Michael Rubinstein and Xiling Shen
  • Epigenetic cell reprogramming in situ: A novel tool for regenerative engineering, Guillermo Ameer, Northwestern University, with Panagiotis Ntziachristos and Hariharan Subramanian
  • Epigenomic regulation over multiple length scales: Understanding chromatin modifications through label free imaging and multi-scale modeling, Juan De Pablo, University of Chicago, with Ali Shilatifard and Hao Zhang
  • Human cardiac opto-epigenetics with HDAC inhibitors, Emilia Entcheva, George Washington University, with Shu Jia, Zhenyu Li, Ralph Mazitschek and Alejandro Villagra
  • Macrogenomic engineering via modulation of chromatin nanoenvironment, Vadim Backman, Northwestern University, with Michael Kennedy, Hemant Roy and Igal Szleifer
  • Optically controlled localized epigenetic chromatin remodeling with photoactivatable CRISPR-dCas9, Lev Perelman, Beth Israel Deaconess Medical Center, with Irving Itzkan, J. Thomas Lamont, Le Qiu and Darren Roblyer
  • Sculpting the genome by design: Epigenetic and chromatin looping inputs to measure and manipulate chromatin organization and dynamics, Megan King, Yale University, with Simon G. Mochrie and Corey O'Hern


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