Loss of Nucleolar Histone Chaperone NPM1 Triggers Rearrangement of Heterochromatin and Synergizes with a Deficiency in DNA Methyltransferase DNMT3A to Drive Ribosomal DNA Transcription

Olausson, Karl Holmberg; Nistér, Monica; Lindström, Mikael S.

doi:10.1074/jbc.m114.569244

Cited by 56 publications

(61 citation statements)

References 83 publications

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“…In somatic cells, NPM1 − one of the NPM2 homologs − undergoes phase separation in a concentration-dependent manner together with the arginine-rich proteins and rRNAs that are required for ribosome biogenesis. This event is critical for structural organization of the somatic nucleoli and, presumably, required to control the activity of ribosome biogenesis (Feric et al, 2016;Holmberg Olausson et al, 2014;Mitrea et al, 2016). In our study, we found that NPM2 has the ability to form a spherical body together with other proteins and RNAs in a concentration-dependent manner.…”

Section: (N>3 Each) (B) Npm2 Protein Expression Levels Inmentioning

confidence: 48%

Reconstitution of the oocyte nucleolus in mice through a single nucleolar protein, NPM2

Ogushi

Yamagata²,

Obuse

et al. 2017

Journal of Cell Science

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The mammalian oocyte nucleolus, the most prominent subcellular organelle in the oocyte, is vital in early development, yet its key functions and constituents remain unclear. We show here that the parthenotes/zygotes derived from enucleolated oocytes exhibited abnormal heterochromatin formation around parental pericentromeric DNAs, which led to a significant mitotic delay and frequent chromosome mis-segregation upon the first mitotic division. A proteomic analysis identified nucleoplasmin 2 (NPM2) as a dominant component of the oocyte nucleolus. Consistently, Npm2-deficient oocytes, which lack a normal nucleolar structure, showed chromosome segregation defects similar to those in enucleolated oocytes, suggesting that nucleolar loss, rather than micromanipulation-related damage to the genome, leads to a disorganization of higher-order chromatin structure in pronuclei and frequent chromosome mis-segregation during the first mitosis. Strikingly, expression of NPM2 alone sufficed to reconstitute the nucleolar structure in enucleolated embryos, and rescued their first mitotic division and full-term development. The nucleolus rescue through NPM2 required the pentamer formation and both the N-and C-terminal domains. Our findings demonstrate that the NPM2-based oocyte nucleolus is an essential platform for parental chromatin organization in early embryonic development.

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Section: (N>3 Each) (B) Npm2 Protein Expression Levels Inmentioning

confidence: 48%

Reconstitution of the oocyte nucleolus in mice through a single nucleolar protein, NPM2

Ogushi

Yamagata²,

Obuse

et al. 2017

Journal of Cell Science

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“…In human colon carcinoma cells lacking DNMT1 or DNMT3B, the levels of the 47S primary rRNA transcript are significantly increased (181). In glioblastoma cells deficient in NPM1, a nucleolar histone chaperone, loss of DNMT3 also synergistically enhances rDNA transcription (180). Indeed, low levels of DNA methylation at rDNA genes are found in many African American women with endometrial carcinoma (178).…”

Section: Disease Progressionmentioning

confidence: 96%

“…rDNA hypomethylation is found in a wide range of cancers, such as hepatocellular carcinoma, endo-metrial cancer, brain cancer, and colon cancer (178)(179)(180)(181). Human hepatocellular carcinoma cells display DNA hypomethylation at rDNA promoters that coincides with the reactivation of silenced rDNA expression (181).…”

Section: Disease Progressionmentioning

confidence: 99%

The Epigenetic Pathways to Ribosomal DNA Silencing

Srivastava

Ahn

2016

Microbiol Mol Biol Rev

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SUMMARYHeterochromatin is the transcriptionally repressed portion of eukaryotic chromatin that maintains a condensed appearance throughout the cell cycle. At sites of ribosomal DNA (rDNA) heterochromatin, epigenetic states contribute to gene silencing and genome stability, which are required for proper chromosome segregation and a normal life span. Here, we focus on recent advances in the epigenetic regulation of rDNA silencing inSaccharomyces cerevisiaeand in mammals, including regulation by several histone modifications and several protein components associated with the inner nuclear membrane within the nucleolus. Finally, we discuss the perturbations of rDNA epigenetic pathways in regulating cellular aging and in causing various types of diseases.

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“…Integration of NPM1 into the nucleolus is dependent on its multivalent interactions with RNA and proteins containing arginine-rich linear motifs (Mitrea et al, 2016). Furthermore, loss of NPM1 triggers rearrangement of perinucleolar heterochromatin (Holmberg Olausson et al, 2014;Murano et al, 2008), suggesting direct interactions between NPM1 and heterochromatin.…”

Section: Cutandrunrnase Probes the Requirement Of Architectural Rna Inmentioning

confidence: 99%

Architectural RNA is required for heterochromatin organization

Thakur

Llagas

et al. 2019

Preprint

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In addition to its known roles in protein synthesis and enzyme catalysis, RNA has been proposed to stabilize higher-order chromatin structure. To distinguish presumed architectural roles of RNA from other functions, we applied a ribonuclease digestion strategy to our CUT&RUN in situ chromatin profiling method (CUT&RUN.RNase). We find that depletion of RNA compromises association of the murine nucleolar protein Nucleophosmin with pericentric heterochromatin and alters the chromatin environment of CCCTC-binding factor (CTCF) bound regions. Strikingly, we find that RNA maintains the integrity of both constitutive (H3K9me3 marked) and facultative (H3K27me3 marked) heterochromatic regions as compact domains, but only moderately stabilizes euchromatin. To establish the specificity of heterochromatin stabilization by RNA, we performed CUT&RUN on cells deleted for the Firre long non-coding RNA and observed disruption of H3K27me3 domains on several chromosomes. We conclude that RNA maintains local and global chromatin organization by acting as a structural scaffold for heterochromatic domains.1

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Loss of Nucleolar Histone Chaperone NPM1 Triggers Rearrangement of Heterochromatin and Synergizes with a Deficiency in DNA Methyltransferase DNMT3A to Drive Ribosomal DNA Transcription

Cited by 56 publications

References 83 publications

Reconstitution of the oocyte nucleolus in mice through a single nucleolar protein, NPM2

Reconstitution of the oocyte nucleolus in mice through a single nucleolar protein, NPM2

The Epigenetic Pathways to Ribosomal DNA Silencing

Architectural RNA is required for heterochromatin organization

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