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The mouse HP1 proteins are essential for preventing liver tumorigenesis

Oncogene volume 39, pages 2676–2691 (2020)Cite this article

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Abstract

Chromatin organization is essential for appropriate interpretation of the genetic information. Here, we demonstrated that the chromatin-associated proteins HP1 are dispensable for hepatocytes survival but are essential within hepatocytes to prevent liver tumor development in mice with HP1β being pivotal in these functions. Yet, we found that the loss of HP1 per se is not sufficient to induce cell transformation but renders cells more resistant to specific stress such as the expression of oncogenes and thus in fine, more prone to cell transformation. Molecular characterization of HP1-Triple KO premalignant livers and BMEL cells revealed that HP1 are essential for the maintenance of heterochromatin organization and for the regulation of specific genes with most of them having well characterized functions in liver functions and homeostasis. We further showed that some specific retrotransposons get reactivated upon loss of HP1, correlating with overexpression of genes in their neighborhood. Interestingly, we found that, although HP1-dependent genes are characterized by enrichment H3K9me3, this mark does not require HP1 for its maintenance and is not sufficient to maintain gene repression in absence of HP1. Finally, we demonstrated that the loss of TRIM28 association with HP1 recapitulated several phenotypes induced by the loss of HP1 including the reactivation of some retrotransposons and the increased incidence of liver cancer development. Altogether, our findings indicate that HP1 proteins act as guardians of liver homeostasis to prevent tumor development by modulating multiple chromatin-associated events within both the heterochromatic and euchromatic compartments, partly through regulation of the corepressor TRIM28 activity.

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Fig. 1: HP1 proteins are essential to prevent tumor development in liver.
Fig. 2: HP1-TKO hepatic cells are viable and have increased potential to cellular transformation upon oncogenic stress.
Fig. 3: HP1 are essential for the maintenance of heterochromatin marks but not to regulate the expression of major satellites.
Fig. 4: HP1 are essential regulators of gene expression in liver.
Fig. 5: HP1 are required for silencing specific endogenous retroviruses (ERVs) in hepatocytes.
Fig. 6: The loss of association between HP1 and TRIM28 partially recapitulates the phenotypes induced by the loss of HP1.

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Acknowledgements

We thank P. Chambon, C. Sardet, T. Forné, D.Fisher, and C. Grimaud for helpful discussions and critical reading of the paper. We thank F. Bernex and L. LeCam, C. Keime, and B. Jost for fruitful discussions. We thank L. Papon, H. Fontaine, and C. Bonhomme for technical assistance and M. Oulad-Abdelghani and the IGBMC for the anti-HP1 and TRIM28 antibodies. We also thank the RHEM technical facility and particularly J. Simony for histological analysis and the IGBMC/ICS transgenic and animal facility for the initial establishment of the HP1 and TRIM28 mouse models. We thank C. Vincent and the IRCM animal core facility for the day to day care of the animal models. Finally, we thank S. Chamroeun for counting positive cells on TMA. We acknowledge the imaging facility MRI, member of the national infrastructure France-BioImaging and supported by the French National Research Agency (ANR-10-INBS-04, «Investments for the future»). This work was supported by funds from the Center National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Montpellier and the Institut regional de Cancérologie de Montpellier (ICM),) and SIRIC Montpellier Cancer, Grant INCa_Inserm_DGOS_12553. SH was funded by an Erasmus Ph.D. fellowship. We also thank the Ministry of Education, Science and Technology of the Republic of Kosovo for a scholarships to support SH. FC was supported by grants from ANR (ANR 2009 BLAN 021 91; ANR-16CE15-0018-03), INCa (PLBIO13-146), ARC (PJA20131200357), and La ligue Régionale contre le Cancer (128-R13021FF-RAB13006FFA). Sequencing was performed by the MGX facility. Montpellier, France.

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  1. These authors contributed equally: Nehmé Saksouk, Shefqet Hajdari

Authors and Affiliations

  1. IRCM, Institut de Recherche en Cancérologie de Montpellier, F-34298, Montpellier, France

    Nehmé Saksouk, Shefqet Hajdari, Yannick Perez, Aliki Zavoriti, Nelly Pirot, Jean-Yohan Noël, Eric Fabbrizio, Eric Julien & Florence M. Cammas

  2. INSERM, U1194, F-34298, Montpellier, France

    Nehmé Saksouk, Shefqet Hajdari, Yannick Perez, Aliki Zavoriti, Nelly Pirot, Jean-Yohan Noël, Eric Fabbrizio, Eric Julien & Florence M. Cammas

  3. Université de Montpellier, F-34090, Montpellier, France

    Nehmé Saksouk, Shefqet Hajdari, Yannick Perez, Aliki Zavoriti, Nelly Pirot, Jean-Yohan Noël, Eric Fabbrizio, Eric Julien & Florence M. Cammas

  4. Institut régional du Cancer de Montpellier, F-34298, Montpellier, France

    Nehmé Saksouk, Shefqet Hajdari, Yannick Perez, Aliki Zavoriti, Nelly Pirot, Jean-Yohan Noël, Lakhdar Khellaf, Eric Fabbrizio, Eric Julien & Florence M. Cammas

  5. MGX, Biocampus Montpellier, CNRS, INSERM, University of Montpellier, Montpellier, France

    Marine Pratlong & Célia Barrachina

  6. IGBMC, Institut de Génétique, de Biologie Moléculaire et Cellulaire, Illkirch, France

    Céline Graber & Amélie Sarrazin

  7. CNRS, Route de Mende, Montpellier, France

    Damien Grégoire, Eric Fabbrizio, Eric Julien & Florence M. Cammas

  8. Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France

    Damien Grégoire

  9. MRI, BioCampus Montpellier, CNRS, INSERM, University of Montpellier, Montpellier, France

    Amélie Sarrazin

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  1. Nehmé Saksouk
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Contributions

NS and SH performed the analysis of mice and interpreted the data. MP and CB made the libraries, generated, and analyzed the RNA-seq data. AZ and EF performed the RT-qPCR experiments. CG participated to mice analysis, NP supervised the histological core facility, and JYN performed the TMA. LK performed the pathological analysis of histological sections. DG was involved in the establishment of BMEL cells. YP and EJ were involved in cell transformation assays and chromatin analysis. FC designed, analyzed, and interpreted the data and wrote the paper with input from all co-authors.

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Correspondence to Florence M. Cammas.

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Saksouk, N., Hajdari, S., Perez, Y. et al. The mouse HP1 proteins are essential for preventing liver tumorigenesis. Oncogene 39, 2676–2691 (2020). https://doi.org/10.1038/s41388-020-1177-8

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