Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer in adults. Among the altered pathways leading to HCC, an increasing role is attributed to abnormal epigenetic regulation. Members of the Heterochromatin Protein (HP1) 1 family are key players in chromatin organisation, acting as docking sites for chromatin modifiers. Here, we inactivated HP1α in HepG2 human liver carcinoma cells and showed that HP1α participated in cell proliferation. HP1α-depleted cells have a global decrease in DNA methylation and consequently a perturbed chromatin organisation, as exemplified by the reactivation of transcription at centromeric and pericentromeric regions, eventhough the protein levels of chromatin writers depositing methylation marks, such as EZH2, SETDB1, SUV39H1, G9A and DNMT3A remained unaltered. This decrease was attributed mainly to a low S-Adenosyl Methionine (SAM) level, a cofactor involved in methylation processes. Furthermore, we showed that this decrease was due to a modification in the Methionine adenosyl transferase 2A RNA (MAT2A) level, which modifies the ratio of MAT1A/MAT2A, two enzymes that generate SAM. Importantly, HP1α reintroduction into HP1α-depleted cells restored the MAT2A protein to its initial level. Finally, we demonstrated that this transcriptional deregulation of MAT2A in HP1α-depleted cells relied on a lack of recruitment of HP1β and HP1γ to MAT2A promoter where an improper non-CpG methylation site was promoted in the vicinity of the transcription start site where HP1β and HP1γ bound. Altogether, these results highlight an unanticipated link between HP1 and the SAM synthesis pathway, and emphasise emerging functions of HP1s as sensors of some aspects of liver cell metabolism.
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Native electrospray ionization mass spectrometry revealed coronaviral polyprotein processing by the viral protease and subsequent complex formation. For further information, see the article by Kirchel and colleagues (pp. 1009–1019) in this issue. The image was in parts created by Anne Rupprecht (Rostock, Germany) and compiled by Boris Krichel. Image provided by Charlotte Uetrecht.
Research Article|
March 13 2020
HP1s modulate the S-Adenosyl Methionine synthesis pathway in liver cancer cells
Maicol Mancini;
Maicol Mancini
Université Montpellier- IRCM, Institut de Recherche en Cancérologie de Montpellier, Inserm, U1194, Campus Val d'Aurelle, F-34298 Montpellier Cedex 5, France
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Laura Papon;
Laura Papon
Université Montpellier- IRCM, Institut de Recherche en Cancérologie de Montpellier, Inserm, U1194, Campus Val d'Aurelle, F-34298 Montpellier Cedex 5, France
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Alain Mangé;
Alain Mangé
Université Montpellier- IRCM, Institut de Recherche en Cancérologie de Montpellier, Inserm, U1194, Campus Val d'Aurelle, F-34298 Montpellier Cedex 5, France
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Florence Cammas;
Florence Cammas
Université Montpellier- IRCM, Institut de Recherche en Cancérologie de Montpellier, Inserm, U1194, Campus Val d'Aurelle, F-34298 Montpellier Cedex 5, France
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Eric Fabbrizio
Université Montpellier- IRCM, Institut de Recherche en Cancérologie de Montpellier, Inserm, U1194, Campus Val d'Aurelle, F-34298 Montpellier Cedex 5, France
Correspondence: Eric Fabbrizio (eric.fabbrizio@inserm.fr)
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Publisher: Portland Press Ltd
Received:
August 26 2019
Revision Received:
February 20 2020
Accepted:
February 24 2020
Accepted Manuscript online:
February 24 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (5): 1033–1047.
Article history
Received:
August 26 2019
Revision Received:
February 20 2020
Accepted:
February 24 2020
Accepted Manuscript online:
February 24 2020
Citation
Maicol Mancini, Laura Papon, Alain Mangé, Florence Cammas, Eric Fabbrizio; HP1s modulate the S-Adenosyl Methionine synthesis pathway in liver cancer cells. Biochem J 13 March 2020; 477 (5): 1033–1047. doi: https://doi.org/10.1042/BCJ20190621
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