Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

Kosuke Yamaguchi; Xiaoying Chen; Brianna Rodgers; Fumihito Miura; Pavel Bashtrykov; Frédéric Bonhomme; Catalina Salinas-Luypaert; Deis Haxholli; Nicole Gutekunst; Bihter Özdemir Aygenli; Laure Ferry; Olivier Kirsh; Marthe Laisné; Andrea Scelfo; Enes Ugur; Paola B. Arimondo; Heinrich Leonhardt; Masato T. Kanemaki; Till Bartke; Daniele Fachinetti; Albert Jeltsch; Takashi Ito; Pierre Antoine Defossez

doi:10.1038/s41467-024-47314-4

Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

Kosuke Yamaguchi, Xiaoying Chen, Brianna Rodgers, Fumihito Miura, Pavel Bashtrykov, Frédéric Bonhomme, Catalina Salinas-Luypaert, Deis Haxholli, Nicole Gutekunst, Bihter Özdemir Aygenli, Laure Ferry, Olivier Kirsh, Marthe Laisné, Andrea Scelfo, Enes Ugur, Paola B. Arimondo, Heinrich Leonhardt, Masato T. Kanemaki, Till Bartke, Daniele FachinettiAlbert Jeltsch, Takashi Ito, Pierre Antoine Defossez

Research output: Contribution to journal › Article › peer-review

Abstract

DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

Original language	English
Article number	2960
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-47314-4
Publication status	Published - 1 Dec 2024
Externally published	Yes

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Yamaguchi, K., Chen, X., Rodgers, B., Miura, F., Bashtrykov, P., Bonhomme, F., Salinas-Luypaert, C., Haxholli, D., Gutekunst, N., Aygenli, B. Ö., Ferry, L., Kirsh, O., Laisné, M., Scelfo, A., Ugur, E., Arimondo, P. B., Leonhardt, H., Kanemaki, M. T., Bartke, T., ... Defossez, P. A. (2024). Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells. Nature Communications, 15(1), Article 2960. https://doi.org/10.1038/s41467-024-47314-4

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title = "Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells",

abstract = "DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.",

author = "Kosuke Yamaguchi and Xiaoying Chen and Brianna Rodgers and Fumihito Miura and Pavel Bashtrykov and Fr{\'e}d{\'e}ric Bonhomme and Catalina Salinas-Luypaert and Deis Haxholli and Nicole Gutekunst and Aygenli, \{Bihter {\"O}zdemir\} and Laure Ferry and Olivier Kirsh and Marthe Laisn{\'e} and Andrea Scelfo and Enes Ugur and Arimondo, \{Paola B.\} and Heinrich Leonhardt and Kanemaki, \{Masato T.\} and Till Bartke and Daniele Fachinetti and Albert Jeltsch and Takashi Ito and Defossez, \{Pierre Antoine\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

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Yamaguchi, K, Chen, X, Rodgers, B, Miura, F, Bashtrykov, P, Bonhomme, F, Salinas-Luypaert, C, Haxholli, D, Gutekunst, N, Aygenli, BÖ, Ferry, L, Kirsh, O, Laisné, M, Scelfo, A, Ugur, E, Arimondo, PB, Leonhardt, H, Kanemaki, MT, Bartke, T, Fachinetti, D, Jeltsch, A, Ito, T & Defossez, PA 2024, 'Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells', Nature Communications, vol. 15, no. 1, 2960. https://doi.org/10.1038/s41467-024-47314-4

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T1 - Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

AU - Yamaguchi, Kosuke

AU - Chen, Xiaoying

AU - Rodgers, Brianna

AU - Miura, Fumihito

AU - Bashtrykov, Pavel

AU - Bonhomme, Frédéric

AU - Salinas-Luypaert, Catalina

AU - Haxholli, Deis

AU - Gutekunst, Nicole

AU - Aygenli, Bihter Özdemir

AU - Ferry, Laure

AU - Kirsh, Olivier

AU - Laisné, Marthe

AU - Scelfo, Andrea

AU - Ugur, Enes

AU - Arimondo, Paola B.

AU - Leonhardt, Heinrich

AU - Kanemaki, Masato T.

AU - Bartke, Till

AU - Fachinetti, Daniele

AU - Jeltsch, Albert

AU - Ito, Takashi

AU - Defossez, Pierre Antoine

PY - 2024/12/1

Y1 - 2024/12/1

N2 - DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

AB - DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

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DO - 10.1038/s41467-024-47314-4

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AN - SCOPUS:85189807956

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2960

ER -

Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

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