Genomes can now be entrusted to store information about a variety of transient biological events in living cells as they happen, much like a flight recorder collects data from an airplane.
“Our method, called ENGRAM, aims to turn cells into their own historians,” said Dr. Jay Shendure, professor of genome sciences at the University of Washington School of Medicine and scientific director of the Brotman Baty Institute for Precision. Medicine. Shendure led the effort, along with Wei Chen, a former graduate student, and Junhong Choi, a former postdoctoral researcher. Junhong Choi is now an assistant investigator at Memorial Sloan Kettering Cancer Center in New York.
ENGRAM stands for multiplexed enhancer-driven genomic recording of transcriptional activity. The acronym is inspired by a neuroscientific term that refers to the physical basis of a memory.
A proof-of-concept report demonstrating some of ENGRAM’s capabilities is published today, July 17, in Nature.
“ENGRAM links any type of biological signal or event to a symbolic barcode. This approach provides a new method for registration and complements previously developed molecular registration techniques.” said Wei Chen, who is now a postdoctoral researcher at the UW Medicine Institute for Protein Design.
This new strategy tracks and archives the type and timing of biological signals by inserting this information into the genome. For example, this could include keeping track of the commands that turn genes on or off. Such recordings could hold clues about what’s happening inside stem cells and prompt them to become different cell types. It can also provide insight into other questions about how cells work and how their past influences their future.
Shendure said creating a biological record of cellular activities is an old idea. However, researchers had encountered problems measuring more than a handful of signals in the same system, and recording the order in which multiple signals occurred.
A few years ago, Choi, Shendure and their colleagues overcame some of these obstacles with a method called DNA Typewriter. This system allowed researchers to write many symbols on the DNA in an orderly manner. However, the challenge remained as to how to encode the biological meaning of each symbol.
“DNA Typewriter is analogous to a keyboard with many symbols. With ENGRAM we make those symbols specific to different biological signals of interest,” Shendure said.
In today’s Nature article, Shendure and his team described how symbolic recording can track the actions of non-coding DNA regions that control protein production from neighboring genes. They also showed how ENGRAM and DNA Typewriter can be combined. The scientists were able to record cell type-specific activities of tens to hundreds of these types of gene regulatory elements.
Some of the regions they tracked are part of gene regulatory networks behind different aspects of embryonic development. Other signals they traced mediate cell responses to stress, immune responses to infection and cell survival.
They also applied ENGRAM to make daily recordings of mouse stem cells as they aggregated into embryonic organoids, a laboratory model of mouse prenatal development. ENGRAM could ultimately help answer the question of how, for example, a history of cell signaling events shaped the individual characteristics of a mouse embryo.
“As we were inspired by new developments in CRISPR to develop both the ENGRAM and DNA Typewriter systems, I imagine these articles will inspire others to further improve genomic registration technologies – so that we may one day the entire history of cells,” said Junhong Choi.
The researchers developing ENGRAM say work is still needed to realize what it and related genome-based recording technologies can potentially do.
“This is a strategy for capturing biological information in living systems. It is not specific to any one field such as cancer or neuroscience and will hopefully be useful across the board,” Shendure said.
Shendure noted that the research covered in the article was instrumental in the development of the Seattle Hub for Synthetic Biology, a collaboration launched last December between the Allen Institute, the Chan Zuckerberg Initiative and the University of Washington. The project, of which Shendure is the lead scientific director, is designing new technologies to record the history of cells over time.
The work reported today in Nature was supported by grants from the Paul G. Allen Frontiers Group, Alex’s Lemonade Stand Foundation, and the National Human Genome Research Institute (UM1HG011586, K99HG012973), as well as the Brotman Baty Institute for Precision Medicine. Shendure is an investigator at the Howard Hughes Medical Institute.
