Nucleophosmin 1 cooperates with the methyltransferase DOT1L to preserve peri-nucleolar heterochromatin organization by regulating H3K27me3 levels and DNA repeats expression

Epigenetics & Chromatin

Research

Stefanie Heidrich¹  Shannon Lebel¹  Arquimedes Cheffer¹  Annalisa Izzo¹  Marta Garcia-Miralles¹  Patrick Bovio¹  Tanja Vogel²  Ipek Akol³  Alejandro Villarreal⁴ 

[1] Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Medical Faculty, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany;Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Medical Faculty, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany;Center for Basics in NeuroModulation (NeuroModul Basics), Medical Faculty, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany;Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Medical Faculty, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany;Faculty of Biology, Albert-Ludwigs-University of Freiburg, 79104, Freiburg, Germany;Center for Basics in NeuroModulation (NeuroModul Basics), Medical Faculty, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany;Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Medical Faculty, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany;Laboratorio de Neuropatología Molecular, Facultad de Medicina, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” UBA-CONICET, Universidad de Buenos Aires, 1121, Buenos Aires, Argentina;

关键词: DOT1L;    NPM1;    Histone methylation;    Peri-nucleolar heterochromatin;    Transcription;    Epigenetics;   

DOI  :  10.1186/s13072-023-00511-9

 received in 2023-03-27, accepted in 2023-09-21,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundNPM1 is a phosphoprotein highly abundant in the nucleolus. However, additional nuclear functions have been attributed to NPM1, probably through interaction with other nuclear factors. DOT1L is one interaction partner of NPM1 that catalyzes methylation of histone H3 at lysine 79 (H3K79). DOT1L, playing functional roles in several biological processes, is known for its capability to organize and regulate chromatin. For example, DOT1L modulates DNA repeats expression within peri-nucleolar heterochromatin. NPM1 also affects peri-nucleolar heterochromatin spatial organization. However, it is unclear as of yet whether NPM1 and DOT1L functionally synergize to preserve nucleoli organization and genome stability, and generally, which molecular mechanisms would be involved.ResultsWe characterized the nuclear function of NPM1 on peri-nucleolar heterochromatin organization. We show that (i) monomeric NPM1 interacts preferentially with DOT1L in the nucleus; (ii) NPM1 acts in concert with DOT1L to maintain each other’s protein homeostasis; (iii) NPM1 depletion results in H3K79me2 upregulation and differential enrichment at chromatin binding genes including Ezh2; (iv) NPM1 and DOT1L modulate DNA repeats expression and peri-nucleolar heterochromatin organization via epigenetic mechanisms dependent on H3K27me3.ConclusionsOur findings give insights into molecular mechanisms employed by NPM1 and DOT1L to regulate heterochromatin activity and structural organization around the nucleoli and shed light on one aspect of the complex role of both proteins in chromatin dynamics.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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