Dynamics of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes
- Mohamed Belhocine1,2,3,4,
- Mathieu Simonin3,
- José David Abad Flores1,2,
- Agata Cieslak3,
- Iris Manosalva1,2,
- Lydie Pradel1,2,
- Charlotte Smith3,
- Eve-Lyne Mathieu1,2,
- Guillaume Charbonnier1,3,
- Joost H.A. Martens5,
- Hendrik G. Stunnenberg5,
- Muhammad Ahmad Maqbool6,
- Aneta Mikulasova7,
- Lisa J. Russell8,
- Daniel Rico7,
- Denis Puthier1,2,
- Pierre Ferrier9,
- Vahid Asnafi3 and
- Salvatore Spicuglia1,2
- 1Aix-Marseille University, Inserm, Theories and Approaches of Genomic Complexity (TAGC), UMR1090, 13288 Marseille, France;
- 2Equipe Labellisée Ligue Contre le Cancer, 13288 Marseille, France;
- 3Université de Paris (Descartes), Institut Necker-Enfants Malades (INEM), Institut national de la santé et de la recherche médicale (Inserm) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, 75015 Paris, France;
- 4Molecular Biology and Genetics Laboratory, Dubai, United Arab Emirates;
- 5Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands;
- 6CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Aderley Park, Macclesfield SK104TG, United Kingdom;
- 7Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
- 8Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
- 9Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, 13288 Marseille, France
Abstract
Broad domains of H3K4 methylation have been associated with consistent expression of tissue-specific, cell identity, and tumor suppressor genes. Here, we identified broad domain–associated genes in healthy human thymic T cell populations and a collection of T cell acute lymphoblastic leukemia (T-ALL) primary samples and cell lines. We found that broad domains are highly dynamic throughout T cell differentiation, and their varying breadth allows the distinction between normal and neoplastic cells. Although broad domains preferentially associate with cell identity and tumor suppressor genes in normal thymocytes, they flag key oncogenes in T-ALL samples. Moreover, the expression of broad domain–associated genes, both coding and noncoding, is frequently deregulated in T-ALL. Using two distinct leukemic models, we showed that the ectopic expression of T-ALL oncogenic transcription factor preferentially impacts the expression of broad domain–associated genes in preleukemic cells. Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extent and number of broad domains. Our results show that the regulation of broad H3K4me3 domains is associated with leukemogenesis, and suggest that the presence of these structures might be used for epigenetic prioritization of cancer-relevant genes, including long noncoding RNAs.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.266924.120.
- Received June 15, 2020.
- Accepted May 5, 2021.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
