Samantha Pattenden, Ph.D.
Associate Professor, Center for Integrative Chemical Biology and Drug Discovery
3214 Marsico Hall, 125 Mason Farm Road, CB# 7363, Chapel Hill, NC, 27599-7363
ACCEPTING DOCTORAL STUDENTS
The Pattenden lab is focused on the development of innovative techniques in chromatin-based therapeutic target discovery and cancer diagnostics. As Director of Applied Epigenetic Screening Technologies at the Center for Integrative Chemical Biology and Drug Discovery, my goal is to enable collaborators to apply chemical biology to the discovery of novel molecular targets, pathways and mechanisms. Our central strategy exploits tumor-specific changes in chromatin accessibility, a universal feature that is directly linked with transcriptional activation, DNA damage repair, replication, RNA processing, and nuclear organization. Since chromatin accessibility offers a comprehensive overview of the rewiring of transcriptional networks that accompanies processes such as cellular differentiation, tumor growth, metastasis, and therapeutic resistance, it is frequently more reliable in predicting cell behavior than gene expression profiles alone.
Chromatin accessibility as a platform for cancer diagnostics and therapeutic discovery
Chromatin-associated proteins frequently occur as modular subunits of various protein complexes with non-overlapping activities within the cell. For this reason, hit compounds derived from typical in vitro screens based on a single domain of a chromatin-associated protein are likely to have limited efficacy or significant off-target effects when tested in vivo. Currently, however, there are very few in vivo chromatin-based assays that are suitable for high throughput screening campaigns. We and others have demonstrated that characteristic chromatin accessibility patterns in tumors can change following treatment with small molecule inhibitors. Consequently, chromatin accessibility could serve as a strategy to screen for chemical inhibitors, to assess pharmacodynamics, and to establish biomarkers for preclinical and clinical trials. In collaboration with Dr. Ian Davis (UNC, Genetics), we have developed a novel high throughput screen for small molecule inhibitors of aberrant chromatin accessibility in cancer. This approach enables discovery of compounds that affect an underlying chromatin defect without a priori target selection, which avoids the pitfalls associated with in vitro chromatin-associated protein screens. To assess the diagnostic potential of chromatin accessibility patterns in tumor cells, we invented a method for extraction of chromatin from formalin fixed, paraffin embedded (FFPE) tissue, which incorporates a patented cavitation enhancement reagent from Dr. Paul Dayton (UNC, Biomedical Engineering). We demonstrated the utility of this cavitation enhancement reagent for fragmentation of genomic DNA in high throughput sequencing applications, chromatin extraction from fixed cells for chromatin immunoprecipitation assays, and extraction of high-quality chromatin from FFPE tissue for identification of tumor-specific chromatin accessibility patterns.
(full citation list available here)
- Cavitation enhancement increases the efficiency and consistency of chromatin fragmentation from fixed cells for downstream quantitative applications.
- High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility.
- A Role for Widely Interspaced Zinc Finger (WIZ) in Retention of the G9a Methyltransferase on Chromatin.
- Cavitation Enhancing Nanodroplets Mediate Efficient DNA Fragmentation in a Bench Top Ultrasonic Water Bath.
- A chemical tool for in vitro and in vivo precipitation of lysine methyltransferase G9a.
- The application of enhanced cavitation to enable DNA and chromatin extraction from archived tissues
- Development of a screen for compounds that target ALT cancer
- Development of a first-in-class high throughput assay based on chromatin accessibility