EPFL BioE Talks SERIES "Reprogramming Transcription Factors With a Universal Zinc Finger Model for Safe and Limitless Epigenetic Editing"
Event details
| Date | 25.03.2024 |
| Hour | 12:15 › 13:15 |
| Speaker | Prof. Marcus B. Noyes, Institute for Systems Genetics, Dept. of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York City, NY (USA) |
| Location | Online |
| Category | Conferences - Seminars |
| Event Language | English |
WEEKLY EPFL BIOE TALKS SERIES (sandwiches provided)
Abstract:
Genome and epi-editing tools have revolutionized research today and provide powerful therapeutic potential due to their high efficacy and ease of use. The ease of use is the result of the simple code used by CRISPR-cas systems that only require the design of a piece of RNA that is complementary to the desired DNA target. As a result, tools ranging from artificial activators and repressors to designer nucleases, recombinases, base editors, and more have been developed by harnessing the programmability of the Cas9 RNA-DNA hybrid to direct these functions to specific sequences in the genome. Nature, on the other hand, has primarily used protein-DNA interactions to direct functions to specific positions in a genome. In fact, more than 75% of the human transcription factors (TFs) use one of just six different kinds of DNA-binding domains (DBDs). For example, the Cys2His2 zinc finger domain (ZF) is by far the most common DBD used by eukaryotes, representing approximately 50% of the human TFs.
Interestingly, the ZF domain was one of the first domains used for these synthetic, programmable purposes but failed to catch on due to the laborious engineering process required to generate novel proteins. However, a simple model of ZF design would unlock the advantages of this smaller domain that would function more similar to natural TFs. For this reason, we screened more than 50 billion protein-DNA interactions to understand how ZFs within arrays engage the DNA. We used this data to train the first AI-based model for ZF design that enables the simple generation of ZF arrays able to bind any target of interest. We have shown that these ZFs can be used to reprogram natural TFs, or TFs with synthetic effector domains, and direct their unique regulatory potential to desired genomic loci. Next, in unpublished work, we used the screen of hundreds of ZF proteins for their ability to bind millions of DNA sequences to retrain the model and improve its prediction of specificity. Ultimately, we are using a combination of synthetic biology, high throughput screens, and machine learning to provide a continuous model of ZFs that enables the design of domains with any desired specificity or kinetic parameter that would impact ZF function across the genome.
Bio:
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IN CASE you cannot attend in-person in the room, please make sure to
Abstract:
Genome and epi-editing tools have revolutionized research today and provide powerful therapeutic potential due to their high efficacy and ease of use. The ease of use is the result of the simple code used by CRISPR-cas systems that only require the design of a piece of RNA that is complementary to the desired DNA target. As a result, tools ranging from artificial activators and repressors to designer nucleases, recombinases, base editors, and more have been developed by harnessing the programmability of the Cas9 RNA-DNA hybrid to direct these functions to specific sequences in the genome. Nature, on the other hand, has primarily used protein-DNA interactions to direct functions to specific positions in a genome. In fact, more than 75% of the human transcription factors (TFs) use one of just six different kinds of DNA-binding domains (DBDs). For example, the Cys2His2 zinc finger domain (ZF) is by far the most common DBD used by eukaryotes, representing approximately 50% of the human TFs.
Interestingly, the ZF domain was one of the first domains used for these synthetic, programmable purposes but failed to catch on due to the laborious engineering process required to generate novel proteins. However, a simple model of ZF design would unlock the advantages of this smaller domain that would function more similar to natural TFs. For this reason, we screened more than 50 billion protein-DNA interactions to understand how ZFs within arrays engage the DNA. We used this data to train the first AI-based model for ZF design that enables the simple generation of ZF arrays able to bind any target of interest. We have shown that these ZFs can be used to reprogram natural TFs, or TFs with synthetic effector domains, and direct their unique regulatory potential to desired genomic loci. Next, in unpublished work, we used the screen of hundreds of ZF proteins for their ability to bind millions of DNA sequences to retrain the model and improve its prediction of specificity. Ultimately, we are using a combination of synthetic biology, high throughput screens, and machine learning to provide a continuous model of ZFs that enables the design of domains with any desired specificity or kinetic parameter that would impact ZF function across the genome.
Bio:
- 2015- Professor at the NYU School of Medicine, focused on protein engineering for systems and synthetic biology applications
- 2009-2015 Started first independent lab as a Lewis-Sigler Fellow, Princeton University, NJ, USA
- 2003-2009 PhD student in Biochemistry at the University of Massachusetts School of Medicine, Worcester, MA, USA
- 1998-2002 Studied Biology and Psychology at Hamline University, St. Paul, MN, USA
- 1990-1998 Played in bad punk rock bands in Minneapolis, MN, USA
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IN CASE you cannot attend in-person in the room, please make sure to
- send D. Reinhard a note well ahead of time (ideally before seminar day), informing that you plan to attend the talk online, and, during seminar:
- be signed in on Zoom with a recognizable user name (not any alias making it difficult or impossible to identify you).
Practical information
- Informed public
- Registration required
Organizer
- Prof. Bart Deplancke, EPFL
Contact
- Institute of Bioengineering (IBI), Dietrich REINHARD