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Grant Details

Grant Number: 5R21CA191186-04 Interpret this number
Primary Investigator: Bailey, Ryan
Organization: University Of Michigan At Ann Arbor
Project Title: Droplet Microfluidic Platform for Ultralow Input Epigenetics
Fiscal Year: 2017


 DESCRIPTION (provided by applicant): 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.


Plug-in tubes allow tunable oil removal, droplet packing, and reaction incubation for time-controlled droplet-based assays.
Authors: Sun M. , Maryu G. , Wang S. , Yang Q. , Bailey R.C. .
Source: Biomicrofluidics, 2021 Mar; 15(2), p. 024108.
EPub date: 2021-04-05.
PMID: 33841602
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Translational Opportunities for Microfluidic Technologies to Enable Precision Epigenomics.
Authors: Xu Y. , Doonan S.R. , Ordog T. , Bailey R.C. .
Source: Analytical chemistry, 2020-06-16; 92(12), p. 7989-7997.
EPub date: 2020-06-04.
PMID: 32496751
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Ionophore-Based Biphasic Chemical Sensing in Droplet Microfluidics.
Authors: Wang X. , Sun M. , Ferguson S.A. , Hoff J.D. , Qin Y. , Bailey R.C. , Meyerhoff M.E. .
Source: Angewandte Chemie (International ed. in English), 2019-06-11; 58(24), p. 8092-8096.
EPub date: 2019-05-08.
PMID: 30997728
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Droplet CAR-Wash: continuous picoliter-scale immunocapture and washing.
Authors: Doonan S.R. , Lin M. , Bailey R.C. .
Source: Lab on a chip, 2019-04-23; 19(9), p. 1589-1598.
PMID: 30963149
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Droplet Microfluidics in Thermoplastics: Device Fabrication, Droplet Generation, and Content Manipulation using Integrated Electric and Magnetic Fields.
Authors: Sahore V. , Doonan S.R. , Bailey R.C. .
Source: Analytical methods : advancing methods and applications, 2018-09-21; 10(35), p. 4264-4274.
EPub date: 2018-08-20.
PMID: 30886651
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A droplet microfluidic platform for efficient enzymatic chromatin digestion enables robust determination of nucleosome positioning.
Authors: Xu Y. , Lee J.H. , Li Z. , Wang L. , Ordog T. , Bailey R.C. .
Source: Lab on a chip, 2018-08-21; 18(17), p. 2583-2592.
PMID: 30046796
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K-Channel: A Multifunctional Architecture for Dynamically Reconfigurable Sample Processing in Droplet Microfluidics.
Authors: Doonan S.R. , Bailey R.C. .
Source: Analytical chemistry, 2017-04-04; 89(7), p. 4091-4099.
EPub date: 2017-03-13.
PMID: 28222260
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Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.
Authors: Tang C.M. , Lee T.E. , Syed S.A. , Burgoyne A.M. , Leonard S.Y. , Gao F. , Chan J.C. , Shi E. , Chmielecki J. , Morosini D. , et al. .
Source: Oncotarget, 2016-11-29; 7(48), p. 78226-78241.
PMID: 27793025
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Genome-Wide Epigenetic Studies in Human Disease: A Primer on -Omic Technologies.
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EPub date: 2015-12-30.
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