Regulation and Roles of the Nucleolus in Embryonic Stem Cells: From Ribosome Biogenesis to Genome Organization

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2020 Sep 25

PMID 32976768

Citations 29

Authors

Shivani Gupta

Raffaella Santoro

Affiliations

Soon will be listed here.

Abstract

The nucleolus is the largest compartment of the eukaryotic cell's nucleus. It acts as a ribosome factory, thereby sustaining the translation machinery. The nucleolus is also the subnuclear compartment with the highest transcriptional activity in the cell, where hundreds of ribosomal RNA (rRNA) genes transcribe the overwhelming majority of RNAs. The structure and composition of the nucleolus change according to the developmental state. For instance, in embryonic stem cells (ESCs), rRNA genes display a hyperactive transcriptional state and open chromatin structure compared with differentiated cells. Increasing evidence indicates that the role of the nucleolus and rRNA genes might go beyond the control of ribosome biogenesis. One such role is linked to the genome architecture, since repressive domains are often located close to the nucleolus. This review highlights recent findings describing how the nucleolus is regulated in ESCs and its role in regulating ribosome biogenesis and genome organization for the maintenance of stem cell identity.

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References

Pelletier J, Thomas G, Volarevic S . Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer. 2017; 18(1):51-63. DOI: 10.1038/nrc.2017.104. View

Meshorer E, Yellajoshula D, George E, Scambler P, Brown D, Misteli T . Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell. 2006; 10(1):105-16. PMC: 1868458. DOI: 10.1016/j.devcel.2005.10.017. View

van Steensel B, Belmont A . Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin, and Gene Repression. Cell. 2017; 169(5):780-791. PMC: 5532494. DOI: 10.1016/j.cell.2017.04.022. View

Guetg C, Santoro R . Formation of nuclear heterochromatin: the nucleolar point of view. Epigenetics. 2012; 7(8):811-4. PMC: 3427276. DOI: 10.4161/epi.21072. View

Percharde M, Lin C, Yin Y, Guan J, Peixoto G, Bulut-Karslioglu A . A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity. Cell. 2018; 174(2):391-405.e19. PMC: 6046266. DOI: 10.1016/j.cell.2018.05.043. View

Bizhanova A, Yan A, Yu J, Zhu L, Kaufman P . Distinct features of nucleolus-associated domains in mouse embryonic stem cells. Chromosoma. 2020; 129(2):121-139. PMC: 7265113. DOI: 10.1007/s00412-020-00734-9. View

Hein N, Hannan K, George A, Sanij E, Hannan R . The nucleolus: an emerging target for cancer therapy. Trends Mol Med. 2013; 19(11):643-54. DOI: 10.1016/j.molmed.2013.07.005. View

Lieberman-Aiden E, van Berkum N, Williams L, Imakaev M, Ragoczy T, Telling A . Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009; 326(5950):289-93. PMC: 2858594. DOI: 10.1126/science.1181369. View

Fulka H, Langerova A . Nucleoli in embryos: a central structural platform for embryonic chromatin remodeling?. Chromosome Res. 2018; 27(1-2):129-140. DOI: 10.1007/s10577-018-9590-3. View

10.

Fadloun A, Le Gras S, Jost B, Ziegler-Birling C, Takahashi H, Gorab E . Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA. Nat Struct Mol Biol. 2013; 20(3):332-8. DOI: 10.1038/nsmb.2495. View

11.

Becker J, McCarthy R, Sidoli S, Donahue G, Kaeding K, He Z . Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes. Mol Cell. 2017; 68(6):1023-1037.e15. PMC: 5858919. DOI: 10.1016/j.molcel.2017.11.030. View

12.

Boisvert F, van Koningsbruggen S, Navascues J, Lamond A . The multifunctional nucleolus. Nat Rev Mol Cell Biol. 2007; 8(7):574-85. DOI: 10.1038/nrm2184. View

13.

Santoro R, Grummt I . Molecular mechanisms mediating methylation-dependent silencing of ribosomal gene transcription. Mol Cell. 2001; 8(3):719-25. DOI: 10.1016/s1097-2765(01)00317-3. View

14.

Strom A, Emelyanov A, Mir M, Fyodorov D, Darzacq X, Karpen G . Phase separation drives heterochromatin domain formation. Nature. 2017; 547(7662):241-245. PMC: 6022742. DOI: 10.1038/nature22989. View

15.

Kempfer R, Pombo A . Methods for mapping 3D chromosome architecture. Nat Rev Genet. 2019; 21(4):207-226. DOI: 10.1038/s41576-019-0195-2. View

16.

Woolnough J, Atwood B, Liu Z, Zhao R, Giles K . The Regulation of rRNA Gene Transcription during Directed Differentiation of Human Embryonic Stem Cells. PLoS One. 2016; 11(6):e0157276. PMC: 4907514. DOI: 10.1371/journal.pone.0157276. View

17.

Guetg C, Lienemann P, Sirri V, Grummt I, Hernandez-Verdun D, Hottiger M . The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats. EMBO J. 2010; 29(13):2135-46. PMC: 2905252. DOI: 10.1038/emboj.2010.17. View

18.

Vertii A, Ou J, Yu J, Yan A, Pages H, Liu H . Two contrasting classes of nucleolus-associated domains in mouse fibroblast heterochromatin. Genome Res. 2019; 29(8):1235-1249. PMC: 6673712. DOI: 10.1101/gr.247072.118. View

19.

Nichols J, Smith A . Naive and primed pluripotent states. Cell Stem Cell. 2009; 4(6):487-92. DOI: 10.1016/j.stem.2009.05.015. View

20.

Bulut-Karslioglu A, Macrae T, Oses-Prieto J, Covarrubias S, Percharde M, Ku G . The Transcriptionally Permissive Chromatin State of Embryonic Stem Cells Is Acutely Tuned to Translational Output. Cell Stem Cell. 2018; 22(3):369-383.e8. PMC: 5836508. DOI: 10.1016/j.stem.2018.02.004. View