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Nat Genet. 2019 Jun;51(6):1060-1066. doi: 10.1038/s41588-019-0424-9. Epub 2019 May 31.

High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer.

Author information

1
HiFiBiO SAS, Paris, France.
2
Laboratoire de Biochimie, CNRS UMR8231, ESPCI Paris, PSL University, Paris, France.
3
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
CNRS UMR3244, Institut Curie, PSL University, Paris, France.
5
Translational Research Department Institut Curie, PSL University, Paris, France.
6
Unicancer, Paris, France.
7
Institut Curie Genomics of Excellence Platform, PSL University, Paris, France.
8
INSERM U932, Institut Curie, PSL University, Paris, France.
9
Surgical Department, Institut Curie, Paris, France.
10
Institut Pasteur, Paris, France.
11
Bayer AG, Leverkusen, Germany.
12
HiFiBiO Inc., Cambridge, MA, USA.
13
Laboratoire de Biochimie, CNRS UMR8231, ESPCI Paris, PSL University, Paris, France. andrew.griffiths@espci.fr.
14
CNRS UMR3244, Institut Curie, PSL University, Paris, France. celine.vallot@curie.fr.
15
Translational Research Department Institut Curie, PSL University, Paris, France. celine.vallot@curie.fr.
16
HiFiBiO SAS, Paris, France. a.gerard@hifibio.com.

Abstract

Modulation of chromatin structure via histone modification is a major epigenetic mechanism and regulator of gene expression. However, the contribution of chromatin features to tumor heterogeneity and evolution remains unknown. Here we describe a high-throughput droplet microfluidics platform to profile chromatin landscapes of thousands of cells at single-cell resolution. Using patient-derived xenograft models of acquired resistance to chemotherapy and targeted therapy in breast cancer, we found that a subset of cells within untreated drug-sensitive tumors share a common chromatin signature with resistant cells, undetectable using bulk approaches. These cells, and cells from the resistant tumors, have lost chromatin marks-H3K27me3, which is associated with stable transcriptional repression-for genes known to promote resistance to treatment. This single-cell chromatin immunoprecipitation followed by sequencing approach paves the way to study the role of chromatin heterogeneity, not just in cancer but in other diseases and healthy systems, notably during cellular differentiation and development.

PMID:
31152164
DOI:
10.1038/s41588-019-0424-9
[Indexed for MEDLINE]

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