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Dr. Pierre Billon - New approaches for the study of human genetic diseases using precision genome editing



Pierre Billon

Columbia University Medical Center, New York

New approaches for the study of human genetic diseases using precision genome editing

Genome editing technologies have profoundly transformed our ability to engineer desired genomic changes within living systems for basic research and therapeutic purposes. However, standard CRISPR-mediated gene disruption strategies rely on the introduction of toxic DNA double-strand breaks (DSB). To overcome this limitation, we developed a DSB-free gene disruption method that relies on base editing to efficiently inactivate genes by precisely converting four codons into STOP codons (Billon et al. Mol Cell 2017a). This approach provides a platform for high-throughput loss-of-function screens in biological systems that are sensitive to DSB induction, including DNA repair deficient cells or patient-derived primary cells. In addition, we show that this method is highly efficient to model cancer-associated nonsense mutations for functional studies. Detecting the presence of edited or de novo mutations is challenging as it can require sophisticated and time-consuming experimental approaches or expensive technologies. To solve this problem, we developed a rapid, programmable and highly versatile method for the detection of precision genome editing events and genetic variation. This method enables highly accurate and marker-free quantification of precision genome editing events introduced by CRISPR-dependent homology-directed repair and base editing in various biological systems, such as mammalian cell lines, organoids and tissues. Furthermore, we show that it can be applied to identify oncogenic signatures in cancer mouse models, patient-derived xenografts and blood samples from cancer patients. The ease, speed and cost efficiency of this method facilitates the generation and study of marker-free cellular and animal models for the study of genetic disorders, and expedites the detection of pathogenic variants in pre-clinical and clinical applications. The development of novel approaches for the study of human genetic variation is a critical step towards precision medicine and the development of novel therapies for cancer and inherited genetic disorders.

Selected references

  • Billon P et al. CRISPR-mediated base editing enables efficient disruption of eukaryotic genes through induction of STOP codons. Mol Cell 2017a 67(6):1068-1079
  • Billon P et al. Acetylation of PCNA sliding surface by Eco1 promotes genome stability through homologous recombination. Mol Cell 2017b 65(1):78-90


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13 Jun

11:00 - 12:00

Seminar room - IPBS - Campus 205