Samantha Pattenden, Ph.D.
Associate Professor, Center for Integrative Chemical Biology and Drug Discovery
2079 Genetic Medicine Building, 120 Mason Farm Road, CB# 7363, Chapel Hill, NC, 27599-7363
ACCEPTING DOCTORAL STUDENTS
The Pattenden Lab develops innovative techniques in chromatin-based therapeutic target discovery and cancer diagnostics. Our research program enables discovery of novel molecular targets, pathways and mechanisms. Some of our current projects include:
Development of a cavitation enhancement technology to access archived tissues for epigenetics-based biomedical research
Collaborators: Dr. Ian Davis (Genetics, Pediatric Hematology/Oncology) and Dr. Paul Dayton (Biomedical Engineering)
Innovative new technologies that enable experimentally robust interrogation of epigenetic mechanisms are needed to broaden our understanding of epigenetic regulatory pathways in human development, disease, and therapeutic resistance. Formalin fixed, paraffin embedded (FFPE) tissues contain a wealth of information on human disease, however, extraction of high-quality chromatin (DNA together with associated nuclear proteins) from these samples for use in epigenetic assays has proven virtually impossible. We are exploring the use of a unique cavitation enhancement reagent in simplifying and standardizing chromatin extraction from FFPE tissues, with the goal of making archived biospecimens available for a broad range of epigenetic-based biomedical research.
Development of a First-in-Class High Throughput Assay Based on Chromatin Accessibility
Collaborators: Dr. Ian Davis (Genetics, Pediatric Hematology/Oncology
As appreciation of the importance of chromatin dysregulation in cancers has grown, chromatin regulatory proteins have emerged as promising targets for therapeutic discovery. Unlike alterations to the underlying DNA sequence, changes in chromatin states are both dynamic and reversible. Chromatin-related proteins are challenging targets for small molecule discovery since they frequently associate with multiple complexes with divergent cellular functions. For this reason, hit compounds derived from in vitro screening approaches based on a single chromatin-associated protein domain will likely suffer from significant off-target effects when tested in cells or in vivo.
To address the immediate need for cell-based chromatin screens, we have developed a target agnostic small molecule screening technology that exploits tumor-specific chromatin accessibility states as a relevant and direct functional readout. By targeting chromatin accessibility instead of a single transcription factor or chromatin regulatory protein, the limitations associated with in vitro screening and single protein target identification can be overcome. This screening technique represents a promising new paradigm in oncology drug discovery that will increase our mechanistic knowledge of tumor-specific changes in the epigenome and expand the repertoire of druggable targets.
Collaborators: Dr. Michael Jarster (Chemical Biology and Medicinal Chemistry
Cancerous cells develop a number of mechanisms to evade the checks and balances present in normal cells. One of the mechanisms by which tumor cells become immortal is by maintaining the length of the caps at the ends of chromosomes called telomeres. Telomere length is maintained by telomerase in ~85% of cancers and by the alternative lengthening of telomeres (ALT) pathway in the remaining ~15% of cancers. The ALT pathway is associated with poor prognosis, but the mechanisms by which ALT is induced are not well understood. ALT cells are frequently associated with the formation of extrachromosomal C-circles, which can be used as a readout for ALT activity. We are developing a high throughput assay using targeted small molecule chemical libraries to discover inhibitors of the ALT C-circle phenotype. Hit compounds will inform the key protein players in ALT maintenance and possibly reveal new therapeutic targets for ALT positive cancers.
(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