Epigenomic analyses are playing increasingly prominent roles in the development of personalized strategies for treating cancer. However, the translation of fundamental epigenomic insight to the clinic is wrought with challenges. Take for example the study of post-translational histone protein modifications, which can serve to either promote or repress the transcription of pendant DNA sequences. Analyses of these critically important interactions bridge genomics and proteomics and present significant challenges in the clinical setting. Chromatin immunoprecipitation (ChIP) is the method of choice for analyzing protein-DNA interactions and the basic method involves fragmentation of chromatin, separation of modified proteins using antibodies and magnetic beads, and subsequent analysis of the associated DNA by qPCR or sequencing. While sounding simple, a typical ChIP workflow involves ~30 steps, takes 4+ days, and requires 106-107 cells as input. These requirements significantly limit the applicability of ChIP in a clinical setting-particularly when minimal sampl is available, such as in the analysis of tumor biopsies, stem cells, or circulating tumor cells. Microfluidic devices offer many attractive benefits over traditional macro-scale methods including reduced volume requirements, parallelization capability, and automated operation, which make them particularly well- suited to sample-constrained epigenetic analyses. A handful of recent reports suggest a substantial opportunity for microfluidically-enabled ChIP analyses; however, there is still considerable room for further improvement. We propose to develop a powerful and versatile, droplet microfluidics-based, nanoliter-scale Chromatin ImmunoCapture (nChIC) platform suitable for individualized medicine applications. Droplet microfluidics offer several benefits, including rapid, controlled, and efficient fluid handling, and the capacity to handle variable sample sizes, since devices can accommodate larger samples by simply operating for longer periods of time. Our nChIC platform will incorporate every major step in the ChIP workflow into an automated device, including cell lysis, chromatin digestion, immunocapture, and DNA purification. Importantly, these processes will be carried out at the single cell level, which promises to provide unique insights into epigenomic tumor heterogeneity. Beyond single cells, the unprecedented ability to handle samples of variable input will also facilitate robust validation against traditional ChIP assays to demonstrate broad genomic coverage. Taken together, we feel that the nChIC platform will be a powerful new tool that enables the translation of epigenomic insight into individualized cancer treatment at the point of care.

Public Health Relevance

Epigenomic tests, and in particular assays that probe protein-DNA interactions, are an emerging tool in the development of personalized cancer treatment strategies. Chromatin immunoprecipitation (ChIP) is the gold standard for probing these interactions; however, conventional ChIP is limited in its clinical utility as it requires large celular input (106-107 cells) and is extremely laborious. We propose to develop a transformative nanoliter-scale Chromatin ImmunoCapture (nChIC) platform that will enable highly automated epigenomic studies with an unprecedented capacity to accommodate variable inputs, which will facilitate the analysis of rare cell populations (e.g. tumor biopsies, cancer stem cells, and circulating tumor cells) while also being able to be upscaled to permit robust, side-by-side validation against macroscale ChIP assays.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-Q (O1))
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Divi, Rao L
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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Tang, Chih-Min; Lee, Tracy E; Syed, Sabriya A et al. (2016) Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget :
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