Simultaneous measurement of biochemical phenotypes and gene expression in single cells

Richer, Amanda L.; Riemondy, Kent; Hardie, Lakotah; Hesselberth, Jay R.

doi:10.1101/820233

Cited by 3 publications

References 27 publications

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Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast

Sottnik,

Shackleford,

Richer

et al. 2023

Preprint

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Invasive lobular carcinoma of the breast (ILC) are typically estrogen receptor α (ER)-positive and present with biomarkers of anti-estrogen sensitive disease, but growing laboratory and clinical data, including poor long-term outcomes faced by patients with ILC, suggest endocrine response and ER function are unique in ILC. We previously identified the DNA repair protein Mediator of DNA Damage Checkpoint 1 (MDC1) as an ILC-specific ER co-regulator necessary for ER genomic activity, and that MDC1 co-regulator activity was associated with dysfunctional canonical DNA repair roles of MDC1. To understand these potentially reciprocal activities of MDC1 in ILC, we profiled the MDC1 interactome and found that MDC1 associated proteins in ILC cells mirror a “BRCA-mutant” state lacking MDC1 interaction with key homologous recombination (HR) proteins. Single-cell gene expression and DNA repair activity showed that specific activation of ER:MDC1 target genes was associated with increased PARP-associated DNA repair and decreased HR gene expression. These data suggest that HR is dysfunctional in ILC, which was supported by a lack of DNA damage-induced RAD51 turnover in ILC cells, and an elevated DNA damage response protein signature in a subset of ILC tumors. We tested whether this HR dysfunction could be exploited using PARP inhibition, and found that talazoparib treatment produced a durable growth suppression bothin vitroand in ILC cell line xenograftsin vivo. The ILC-specific ER:MDC1 association creates a new context for ER and MDC1 function in ILC, at the cost of a DNA repair dysfunction that may be therapeutically targetable.SignificanceILC are rarely associated with biomarkers of overt HR deficiency, as such patients are rarely eligible for treatment with PARP inhibitors. Our work suggests ILC present with a previously unappreciated form of HR dysfunction, linked to ILC-specific genomic activity of ER, that imparts sensitivity to PARP inhibition.

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Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast

Sottnik,

Shackleford,

Richer

et al. 2023

Preprint

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clustifyr: An R package for automated single-cell RNA sequencing cluster classification

Gillen

Sheridan

et al. 2019

Preprint

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15Background: In single-cell RNA sequencing (scRNA-seq) analysis, assignment of likely cell 16 types remains a time-consuming, error-prone, and biased process. Current packages for identity 17 assignment use limited types of reference data, and often have rigid data structure 18requirements. As such, a more flexible tool, capable of handling multiple types of reference data 19and data structures, would be beneficial. 20 21Findings: To address difficulties in cluster identity assignment, we developed the clustifyr R 22package. The package leverages external datasets, including gene expression profiles from 23 scRNA-seq, bulk RNA-seq, microarray expression data, and/or signature gene lists, to assign 24 likely cell types. We benchmark various parameters of a correlation-based approach, and also 25 implement a variety of gene list enrichment methods. By providing tools for exploratory data 26 analysis, we demonstrate the feasibility of a simple and effective data-driven approach for cell 27 type assignment in scRNA-seq cell clusters. 28 29 Conclusions: clustifyr is a lightweight and effective cell type assignment tool developed for 30 compatibility with various scRNA-seq analysis workflows. clustifyr is publicly available at 31 https://github.com/rnabioco/clustifyr 32 KEYWORDS 33 Single-cell RNA sequencing, cell type classification, gene expression profile, R package 34 35

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clustifyr: an R package for automated single-cell RNA sequencing cluster classification

Gillen

Sheridan

et al. 2020

F1000Res

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Assignment of cell types from single-cell RNA sequencing (scRNA-seq) data remains a time-consuming and error-prone process. Current packages for identity assignment use limited types of reference data and often have rigid data structure requirements. We developed the clustifyr R package to leverage several external data types, including gene expression profiles to assign likely cell types using data from scRNA-seq, bulk RNA-seq, microarray expression data, or signature gene lists. We benchmark various parameters of a correlation-based approach and implement gene list enrichment methods. clustifyr is a lightweight and effective cell-type assignment tool developed for compatibility with various scRNA-seq analysis workflows. clustifyr is publicly available at https://github.com/rnabioco/clustifyr

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Simultaneous measurement of biochemical phenotypes and gene expression in single cells

Cited by 3 publications

References 27 publications

Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast

Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast

clustifyr: An R package for automated single-cell RNA sequencing cluster classification

clustifyr: an R package for automated single-cell RNA sequencing cluster classification

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