Dynamics of epigenetic plasticity in cancer

Publications

Year of publication 2021

Marsolier, Justine Prompsy, Pacôme Durand, Adeline Lyne, Anne-Marie Landragin, Camille Trouchet, Amandine Bento, Sabrina Tenreira Eisele, Almut Foulon, Sophie Baudre, Léa Grosselin, Kevin Bohec, Mylène Baulande, Sylvain Dahmani, Ahmed Sourd, Laura Letouzé, Eric Marangoni, Elisabetta Perié, Leïla Vallot, Céline (2021 Jan 4)

H3K27me3 is a determinant of chemotolerance in triple-negative breast cancer

bioRxivbioRxiv : DOI : 10.1101/2021.01.04.423386 Learn more
Summary

Triple-negative breast cancer is associated with the worst prognosis and the highest risk of recurrence among all breast cancer subtypes[1][1]. Residual disease, formed by cancer cells persistent to chemotherapy, remains one of the major clinical challenges towards full cure[2][2],[3][3]. There is now consensus that non-genetic processes contribute to chemoresistance in various tumor types, notably through the initial emergence of a reversible chemotolerant state[4][4]–[6][5]. Understanding non-genetic tumor evolution stands now as a prerequisite for the design of relevant combinatorial approaches to delay recurrence. Here we show that the repressive histone mark H3K27me3 is a determinant of cell fate under chemotherapy exposure, monitoring epigenomes, transcriptomes and lineage with single-cell resolution. We identify a reservoir of persister basal cells with EMT markers and activated TGF-β pathway leading to multiple chemoresistance phenotypes. We demonstrate that, in unchallenged cells, H3K27 methylation is a lock to the expression program of persister cells. Promoters are primed with both H3K4me3 and H3K27me3, and removing H3K27me3 is sufficient for their transcriptional activation. Leveraging lineage barcoding, we show that depleting H3K27me3 alters tumor cell fate under chemotherapy insult – a wider variety of tumor cells tolerate chemotherapy. Our results highlight how chromatin landscapes shape the potential of unchallenged cancer cells to respond to therapeutic stress.

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Year of publication 2020

Pacôme Prompsy, Pia Kirchmeier, Justine Marsolier, Marc Deloger, Nicolas Servant, Céline Vallot (2020 Nov 12)

Interactive analysis of single-cell epigenomic landscapes with ChromSCape.

Nature communications : 5702 : DOI : 10.1038/s41467-020-19542-x Learn more
Summary

Chromatin modifications orchestrate the dynamic regulation of gene expression during development and in disease. Bulk approaches have characterized the wide repertoire of histone modifications across cell types, detailing their role in shaping cell identity. However, these population-based methods do not capture cell-to-cell heterogeneity of chromatin landscapes, limiting our appreciation of the role of chromatin in dynamic biological processes. Recent technological developments enable the mapping of histone marks at single-cell resolution, opening up perspectives to characterize the heterogeneity of chromatin marks in complex biological systems over time. Yet, existing tools used to analyze bulk histone modifications profiles are not fit for the low coverage and sparsity of single-cell epigenomic datasets. Here, we present ChromSCape, a user-friendly interactive Shiny/R application distributed as a Bioconductor package, that processes single-cell epigenomic data to assist the biological interpretation of chromatin landscapes within cell populations. ChromSCape analyses the distribution of repressive and active histone modifications as well as chromatin accessibility landscapes from single-cell datasets. Using ChromSCape, we deconvolve chromatin landscapes within the tumor micro-environment, identifying distinct H3K27me3 landscapes associated with cell identity and breast tumor subtype.

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Felix Raimundo, Celine Vallot, Jean-Philippe Vert (2020 Aug 25)

Tuning parameters of dimensionality reduction methods for single-cell RNA-seq analysis.

Genome biology : 212 : DOI : 10.1186/s13059-020-02128-7 Learn more
Summary

Many computational methods have been developed recently to analyze single-cell RNA-seq (scRNA-seq) data. Several benchmark studies have compared these methods on their ability for dimensionality reduction, clustering, or differential analysis, often relying on default parameters. Yet, given the biological diversity of scRNA-seq datasets, parameter tuning might be essential for the optimal usage of methods, and determining how to tune parameters remains an unmet need.

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Year of publication 2019

Kevin Grosselin, Adeline Durand, Justine Marsolier, Adeline Poitou, Elisabetta Marangoni, Fariba Nemati, Ahmed Dahmani, Sonia Lameiras, Fabien Reyal, Olivia Frenoy, Yannick Pousse, Marcel Reichen, Adam Woolfe, Colin Brenan, Andrew D. Griffiths*, Céline Vallot* & Annabelle Gérard* (2019 May 31)

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

Nature Genetics : 51 : 1060–1066 : DOI : 10.1038/s41588-019-0424-9 Learn more
Summary

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.

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Year of publication 2017

Céline Vallot, Catherine Patrat, Amanda J Collier, Christophe Huret, Miguel Casanova, Tharvesh M Liyakat Ali, Matteo Tosolini, Nelly Frydman, Edith Heard, Peter J Rugg-Gunn, Claire Rougeulle (2017 Jan 5)

XACT Noncoding RNA Competes with XIST in the Control of X Chromosome Activity during Human Early Development.

Cell stem cell : 102-111 : DOI : 10.1016/j.stem.2016.10.014 Learn more
Summary

Sex chromosome dosage compensation is essential in most metazoans, but the developmental timing and underlying mechanisms vary significantly, even among placental mammals. Here we identify human-specific mechanisms regulating X chromosome activity in early embryonic development. Single-cell RNA sequencing and imaging revealed co-activation and accumulation of the long noncoding RNAs (lncRNAs) XACT and XIST on active X chromosomes in both early human pre-implantation embryos and naive human embryonic stem cells. In these contexts, the XIST RNA adopts an unusual, highly dispersed organization, which may explain why it does not trigger X chromosome inactivation at this stage. Functional studies in transgenic mouse cells show that XACT influences XIST accumulation in cis. Our findings therefore suggest a mechanism involving antagonistic activity of XIST and XACT in controlling X chromosome activity in early human embryos, and they highlight the contribution of rapidly evolving lncRNAs to species-specific developmental mechanisms.

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Year of publication 2015

Céline Vallot, Jean-François Ouimette, Mélanie Makhlouf, Olivier Féraud, Julien Pontis, Julien Côme, Cécile Martinat, Annelise Bennaceur-Griscelli, Marc Lalande, Claire Rougeulle (2015 Apr 30)

Erosion of X Chromosome Inactivation in Human Pluripotent Cells Initiates with XACT Coating and Depends on a Specific Heterochromatin Landscape.

Cell stem cell : 533-46 : DOI : 10.1016/j.stem.2015.03.016 Learn more
Summary

Human pluripotent stem cells (hPSCs) display extensive epigenetic instability, particularly on the X chromosome. In this study, we show that, in hPSCs, the inactive X chromosome has a specific heterochromatin landscape that predisposes it to erosion of X chromosome inactivation (XCI), a process that occurs spontaneously in hPSCs. Heterochromatin remodeling and gene reactivation occur in a non-random fashion and are confined to specific H3K27me3-enriched domains, leaving H3K9me3-marked regions unaffected. Using single-cell monitoring of XCI erosion, we show that this instability only occurs in pluripotent cells. We also provide evidence that loss of XIST expression is not the primary cause of XCI instability and that gene reactivation from the inactive X (Xi) precedes loss of XIST coating. Notably, expression and coating by the long non-coding RNA XACT are early events in XCI erosion and, therefore, may play a role in mediating this process.

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Year of publication 2014

C Vallot, A Hérault, S Boyle, W A Bickmore, F Radvanyi (2014 Jan 29)

PRC2-independent chromatin compaction and transcriptional repression in cancer.

Oncogene : 741-51 : DOI : 10.1038/onc.2013.604 Learn more
Summary

The silencing of large chromosomal regions by epigenetic mechanisms has been reported to occur frequently in cancer. Epigenetic marks, such as histone methylation and acetylation, are altered at these loci. However, the mechanisms of formation of such aberrant gene clusters remain largely unknown. Here, we show that, in cancer cells, the epigenetic remodeling of chromatin into hypoacetylated domains covered with histone H3K27 trimethylation is paralleled by changes in higher-order chromatin structures. Using fluorescence in situ hybridization, we demonstrate that regional epigenetic silencing corresponds to the establishment of compact chromatin domains. We show that gene repression is tightly correlated to the state of chromatin compaction and not to the levels of H3K27me3-its removal through the knockdown of EZH2 does not induce significant gene expression nor chromatin decompaction. Moreover, transcription can occur with intact high-H3K27me3 levels; treatment with histone deacetylase inhibitors can relieve chromatin compaction and gene repression, without altering H3K27me3 levels. Our findings imply that compaction and subsequent repression of large chromatin domains are not direct consequences of PRC2 deregulation in cancer cells. By challenging the role of EZH2 in aberrant gene silencing in cancer, these findings have therapeutical implications, notably for the choice of epigenetic drugs for tumors with multiple regional epigenetic alterations.

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Year of publication 2013

Céline Vallot, Christophe Huret, Yann Lesecque, Alissa Resch, Noufissa Oudrhiri, Annelise Bennaceur-Griscelli, Laurent Duret, Claire Rougeulle (2013 Jan 22)

XACT, a long noncoding transcript coating the active X chromosome in human pluripotent cells.

Nature genetics : 239-41 : DOI : 10.1038/ng.2530 Learn more
Summary

X-chromosome inactivation (XCI) in mammals relies on XIST, a long noncoding transcript that coats and silences the X chromosome in cis. Here we report the discovery of a long noncoding RNA, XACT, that is expressed from and coats the active X chromosome specifically in human pluripotent cells. In the absence of XIST, XACT is expressed from both X chromosomes in humans but not in mice, suggesting a unique role for XACT in the control of human XCI initiation.

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Year of publication 2010

Céline Vallot, Nicolas Stransky, Isabelle Bernard-Pierrot, Aurélie Hérault, Jessica Zucman-Rossi, Elodie Chapeaublanc, Dimitri Vordos, Agnès Laplanche, Simone Benhamou, Thierry Lebret, Jennifer Southgate, Yves Allory, François Radvanyi (2010 Dec 20)

A novel epigenetic phenotype associated with the most aggressive pathway of bladder tumor progression.

Journal of the National Cancer Institute : 47-60 : DOI : 10.1093/jnci/djq470 Learn more
Summary

Epigenetic silencing can extend to whole chromosomal regions in cancer. There have been few genome-wide studies exploring its involvement in tumorigenesis.

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