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Integrated Single-Cell Analysis Reveals Treatment-Induced Epigenetic Homogenization

56 Pages Posted: 6 Oct 2020 Publication Status: Review Complete

See all articles by Kristof Torkenczy

Kristof Torkenczy

Oregon Health and Science University - Department of Molecular and Medical Genetics

Ellen Langer

Oregon Health and Science University - Department of Molecular and Medical Genetics

Andrew Fields

Oregon Health and Science University - Department of Molecular and Medical Genetics

Megan Turnidge

Oregon Health and Science University - Department of Molecular and Medical Genetics

Andrew Nishida

Oregon Health and Science University - Department of Molecular and Medical Genetics

Christopher Boniface

Oregon Health and Science University - Department of Molecular and Medical Genetics

Paul Spellman

Oregon Health and Science University - Department of Molecular and Medical Genetics

Emek Demir

Oregon Health and Science University - Department of Molecular and Medical Genetics

Joe Gray

Oregon Health and Science University - OHSU Knight Cancer Center Institute

Rosalie Sears

Oregon Health and Science University - Department of Molecular and Medical Genetics

Andrew Adey

Oregon Health and Science University - Department of Molecular and Medical Genetics

More...

Abstract

Triple negative breast cancers (TNBC) constitute one-sixth of invasive female breast cancer cases and are the most likely to develop resistance to treatment via genetic and/or epigenetic adaptation into drug tolerant persister (DTP) states. We applied single-cell ATAC-seq and RNA-seq to characterize the dynamic regulatory and transcriptional landscape in five basal-like TNBC cell lines in response to the MEK inhibitor Trametinib. We observed surprisingly few shared changes between lines, indicating substantial heterogeneity in the emergence of DTP states. However, we identified a shift toward a common state based on the novel observation of the preferential loss of cell line-specific regulatory elements and gene expression. Integration of the two modalities enabled a granular dissection of dynamic regulatory mechanisms, which revealed highly context-dependent roles of regulatory elements. This work highlights the heterogeneity of response, yet suggests homogenization occurs in the form of the preferential loss of epigenetic configurations unique to each BCCL.

Keywords: Single-cell, triple-negative breast cancer, drug response, chromatin accessibility, cell-cell heterogeneity, cell state dynamics

Suggested Citation

Torkenczy, Kristof and Langer, Ellen and Fields, Andrew and Turnidge, Megan and Nishida, Andrew and Boniface, Christopher and Spellman, Paul and Demir, Emek and Gray, Joe and Sears, Rosalie and Adey, Andrew, Integrated Single-Cell Analysis Reveals Treatment-Induced Epigenetic Homogenization. Available at SSRN: https://ssrn.com/abstract=3687026 or http://dx.doi.org/10.2139/ssrn.3687026
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kristof Torkenczy

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Ellen Langer

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Andrew Fields

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Megan Turnidge

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Andrew Nishida

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Christopher Boniface

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Paul Spellman

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Emek Demir

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Joe Gray

Oregon Health and Science University - OHSU Knight Cancer Center Institute ( email )

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

Rosalie Sears

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

Andrew Adey (Contact Author)

Oregon Health and Science University - Department of Molecular and Medical Genetics ( email )

United States

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