Epigenome Editing and Gene Regulation

Although our genome sequence provides the instructions that encode for cell functions, the epigenome – or how the genome is structured, modified, and controlled – determines when and to what level those instructions are implemented. Therefore the epigenome is responsible for determining cell type specification, adaptation to environmental stimuli, and response to drugs and other therapies. The epigenome is also misregulated in many diseases and disorders. Interesting, the epigenome plays a central role in biology, disease, and medicine, but is also very poorly understood. Therefore we are developing epigenome editing technologies to better understand epigenetic regulation and harness its power for cell programming (Thakore et al., Nature Methods 2016). A major emphasis of this work is engineering synthetic enzymes that can be used to precisely manipulate any property of the epigenome, including histone modifications and DNA methylation, at very specific locations within the genomic DNA. We are also using these tools to understand the genetics of common complex disease and the determinants of cell fate decisions. Finally, we are interested in the therapeutic applications of these tools to diverse conditions.  This work is currently largely focused on capitalizing on the power of the CRISPR/Cas9 system to target these epigenetic modifications to specific sites in the genome.

Figure 1 | Applications of epigenome editing. Targeted control over epigenetic regulation is achieved via fusion of programmable DNA-binding domains (DBDs) to epigenome editing effectors. These engineered epigenome editing proteins can be used for basic research, biotechnology and therapeutic applications.

Related works:

1. PI Thakore, JB Black, IB Hilton, CA Gersbach. Editing the Epigenome: Technologies for Programmable Transcription and Epigenetic Modulation. Nature Methods 13(2):127-37 (2016).

2. PI Thakore, AM D’Ippolito, L Song, A Safi, NK Shivakumar, AM Kabadi, TE Reddy, GE Crawford, and CA Gersbach. Highly Specific Epigenome Editing by CRISPR/Cas9 Repressors for Silencing of Distal Regulatory Elements. Nature Methods 12, 1143-1149 (2015).

3. IB Hilton and CA Gersbach. Enabling Functional Genomics with Genome Engineering. Genome Research 25(10):1442-55 (2015).

4. LR Polstein, P Perez-Pinera, DD Kocak, CM Vockley, P Bledsoe, L Song, A Safi, GE Crawford*, TE Reddy*, and CA Gersbach*. Genome-Wide Specificity of DNA-Binding, Gene Regulation, and Chromatin Remodeling by TALE- and CRISPR/Cas9-Based Transcriptional Activators. Genome Research 25(8):1158-69 (2015).

5. IB Hilton, AM D’Ippolito, CM Vockley, PI Thakore, GE Crawford, TE Reddy*, and CA Gersbach*.  Epigenome editing by a CRISPR/Cas9-based acetyltransferase activates genes from promoters and enhancers. Nature Biotechnology 33(5):510-7 (2015).

        -Highlighted by Nature 528:S12 (2015), Nature 520:135 (2015), Nature Biotechnology 33:606–7 (2015), Nature Methods 12:489 (2015), Nature Reviews Molecular Cell Biology 16:266–7 (2015), Molecular Therapy 23:795 (2015), Genome Medicine 7:59 (2015).

6. P Perez-Pinera, DD Kocak, CM Vockley, AF Adler, AM Kabadi, LR Polstein, PI Thakore, KA Glass, DG Ousterout, KW Leong, F Guilak, GE Crawford, TE Reddy, CA Gersbach.  RNA-Guided Gene Activation by CRISPR-Cas9-Based Transcription Factors. Nature Methods 10(10):973-6 (2013).

        -Highlighted by Science 341(6148):833-836 (2013), Molecular Therapy 21(9):1643 (2013), Genetic Engineering and Biotechnology News

7. P Perez-Pinera, DG Ousterout, JM Brunger, AM Farin, KA Glass, F Guilak, GE Crawford, AJ Hartemink, CA Gersbach.  Synergistic and Tunable Human Gene Activation by Combinations of Engineered Transcription Factors. Nature Methods 10(3):239-42 (2013).

        -Highlighted by Nature Methods 10(3):207-8 (2013)