Epigenome Editing as a Tool for Basic Discovery and Therapeutic Intervention

Wednesday, June 5, 2024 | 2:00 to 3:00 p.m. ET

Jonathan Weissman, Ph.D.

Professor of Biology

Core Member, Whitehead Institute

Investigator, Howard Hughes Medical Institute

Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology

weissman@wi.mit.edu

Website

Jonathan Weissman, Ph.D., studies how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. He is also widely recognized for building innovative tools for broadly exploring organizational principles of biological systems. These include ribosome profiling, which globally monitors protein translation, CRISPRi/a for controlling the expression of human genes and rewiring the epigenome, and lineage tracing tools, to record the history of cells.
Dr. Weissman is a member of the Whitehead Institute for Biomedical Research, a Landon T. Clay Professor of Biology Massachusetts Institute of Technology, a member of the Koch Institute for Integrative Cancer Research at MIT, a member of the Ludwig Center for Molecular Oncology, and an Investigator at the Howard Hughes Medical Institute. He is a member of the National Academy of Sciences, a member of the Scientific Advisory Board for Amgen, a member of the President’s Advisory Group for the Chan-Zuckerberg Biohub, and a member of the European Molecular Biology Organization.
Dr. Weissman has received numerous awards including the Beverly and Raymond Sackler International Prize in Biophysics (2008), The Keith Porter Award Lecture from the American Society of Cell Biology (2015), the National Academy Science Award for Scientific Discovery (2015), and the Ira Herskowitz Award from the Genetic Society of America (2020). 

Summary

https://videocast.nih.gov/watch=52301

Genetic medicines hold great promise but are often difficult to translate to the clinic. Current CRISPR-based DNA-editing technologies are complex large molecules that are challenging to deliver and have been associated with unintended editing outcomes. We therefore favored an epigenetic editing approach to permanently turn off prion protein expression in the brain without altering the underlying DNA sequence or leading to continued expression of an altered mRNA and protein. This strategy uses DNA methylation to achieve long-term transcriptional silencing. However, current epigenetic editors are cytotoxic in some circumstances and are too large to fit in an adeno-associated virus (AAV) vector, the preferred delivery vehicle to the central nervous system.

Presentation Objectives:

1. To understand the basic tools for CRISRP-based epigenome editing including CRISPRi, CRISPRa, and CRISPRoff 
2. To understand how these tools can be used to enable exploration of gene function by systematic, information-rich forward genetic approaches.
3. To discuss a new tool termed CHARM which enables programmable silencing of targeted genes.
4. To explore the application of CHARM to treat prion diseases.
5. To explore the potential broader therapeutic applications of CHARM