Initial Genomics of the Human Nucleolus

Németh, Attila; Conesa, Ana; Santoyo-López, Javier; Medina, Ignacio; Montaner, David; Péterfia, Bálint; Solovei, Irina; Cremer, Thomas; Dopazo, Joaquı́n; Längst, Gernot

doi:10.1371/journal.pgen.1000889

Cited by 345 publications

(405 citation statements)

References 51 publications

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“…Genes transcribed by PolI or PolII can be epigenetically silenced (13,(39)(40)(41), and some forms of recombination are also inhibited (42)(43)(44)(45)(46)(47). In higher eukaryotes, the perinucleolar space is associated with heterochromatin (1, 4, 5, 48-50) and poorly expressed genes (7,8). There is, furthermore, evidence that rDNA repeats are prone to clustering in S. pombe because the two rDNA arrays at the ends of chromosome 3 merge in the nucleolus (25) similar to nucleolar fusion in higher eukaryotes (50,51).…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, a DNA element essential for the silencing of the imprinted Kcnq1ot1 locus targets DNA to the perinucleolar space in S phase, and this localization has been suggested to participate in epigenetically silencing the locus (60,61). Recent genomics studies have identified chromatin domains preferentially associated with the nucleolus in human cell lines (7,8). These suggest that the periphery of the nucleolus is a transcription-poor environment that might mediate gene repression by sequestering genes away from more active environments.…”

Section: Resultsmentioning

confidence: 99%

“…In interphase, chromatin domains and entire chromosomes tend to occupy defined positions relative to each other or to nuclear landmarks. Chromosomal regions capable of associating with the nuclear periphery, with nuclear substructures, or with each other have been proposed to function as anchors underlying this organization (4)(5)(6)(7). Coupled with a nonuniform distribution of proteins in the nucleus, the dynamic, directed localization of chromosomal regions to subnuclear compartments might influence and perhaps regulate gene expression and recombination.…”

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Subnuclear relocalization and silencing of a chromosomal region by an ectopic ribosomal DNA repeat

Jakočiūnas¹,

Jordö²,

Mebarek³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Our research addresses the relationship between subnuclear localization and gene expression in fission yeast. We observed the relocalization of a heterochromatic region, the mating-type region, from its natural location at the spindle-pole body to the immediate vicinity of the nucleolus. Relocalization occurred in response to a DNA rearrangement replacing a boundary element (IR-R) with a ribosomal DNA repeat (rDNA-R). Gene expression was strongly silenced in the relocalized mating-type region through mechanisms that differ from those operating in wild type. Also different from the wild-type situation, programmed recombination events failed to take place in the rDNA-R mutant. Increased silencing and perinucleolar localization depended on Reb1, a DNAbinding protein with cognate sites in the rDNA. Reb1 was recently shown to mediate long-range interchromosomal interactions in the nucleus through dimerization, providing a mechanism for the observed relocalization. Replacing the full rDNA repeat with Reb1-binding sites, and using mutants lacking the histone H3K9 methyltransferase Clr4, indicated that the relocalized region was silenced redundantly by heterochromatin and another mechanism, plausibly antisense transcription, achieving a high degree of repression in the rDNA-R strain.nuclear organization | gene silencing | chromatin | boundary elements | antisense transcription E ukaryotic genomes are spatially organized within the nucleus (reviewed in refs. 1-5). In interphase, chromatin domains and entire chromosomes tend to occupy defined positions relative to each other or to nuclear landmarks. Chromosomal regions capable of associating with the nuclear periphery, with nuclear substructures, or with each other have been proposed to function as anchors underlying this organization (4-7). Coupled with a nonuniform distribution of proteins in the nucleus, the dynamic, directed localization of chromosomal regions to subnuclear compartments might influence and perhaps regulate gene expression and recombination. Both stable associations and transient contacts might impose lasting marks on the regions that participate in them (8, 9). Despite our increasingly detailed view of subnuclear organization, however, the two fundamental questions of how the organization is achieved and of its physiological significance remain largely open.In the fission yeast Schizosaccharomyces pombe, extended silent heterochromatic domains are found at the three centromeres, at the telomeres of chromosome 1 and 2, and in the right arm of chromosome 2, in the mating-type region (10-16). Large clusters of rDNA repeats at both ends of chromosome 3 are also partially heterochromatic (13,16). In addition to their distinctive chromatin structures, these regions display distinctive subnuclear localizations. The fission yeast nucleus is structured (17)(18)(19)(20)(21)(22)(23), and the nuclear proteome is not uniformally distributed (24). One pole of the interphase nucleus is defined by the microtubule organizing center or spindle-pole body (SPB) spanning ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Subnuclear relocalization and silencing of a chromosomal region by an ectopic ribosomal DNA repeat

Jakočiūnas¹,

Jordö²,

Mebarek³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to containing the active and inactive rDNA repeats, nucleoli also associate with numerous specific sequences, including satellite repeats, zinc finger proteins, olfactory receptor genes, as well as members of the defensin and Ig gene families. 27,28 These identified nucleolar-associated regions encompassed about 4% of the genome and strongly correlate with low gene density and general transcriptional repression in the tissues examined. Moreover, due to the linear proximity of centromeres to NORs, PCH often colocalizes with PNH.…”

Section: Discussionmentioning

confidence: 99%

Functional redundancy in the nuclear compartmentalization of the late-replicating genome

Ragoczy

Telling

Scalzo

et al. 2014

Nucleus

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The eukaryotic nucleus is structurally and functionally organized, as reflected in the distribution of its protein and DNA components. The genome itself is segregated into euchromatin and heterochromatin that replicate in a distinct spatio-temporal manner. We used a combination of fluorescence in situ hybridization (FISH) and DamID to investigate the localization of the early and late replicating components of the genome in a lymphoblastoid cell background. Our analyses revealed that the bulk of late replicating chromatin localizes to the nuclear peripheral heterochromatin (PH) in a chromosome size and gene density dependent manner. Late replicating DNA on small chromosomes exhibits a much lower tendency to localize to PH and tends to associate with alternate repressive subcompartments such as pericentromeric (PCH) and perinucleolar heterochromatin (PNH). Furthermore, multicolor FISH analysis revealed that late replicating loci, particularly on the smaller chromosomes, may associate with any of these 3 repressive subcompartments, including more than one at the same time. These results suggest a functional equivalence or redundancy among the 3 subcompartments. Consistent with this notion, disruption of nucleoli resulted in an increased association of late replicating loci with peripheral heterochromatin. Our analysis reveals that rather than considering the morphologically distinct PH, PCH and PNH as individual subcompartments, they should be considered in aggregate as a functional compartment for late replicating chromatin.

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“…35 Many genomic loci are closely associated with and are co-purified with the nucleolus. 36,37 The nucleolus is known to promote the silencing of X chromosome through spatial proximity. 38 Therefore, the nucleolar heterochromatin domain may directly facilitate the silencing of non-nucleolar genes.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar repression facilitates initiation and maintenance of senescence

Yang

Song

Soliman³

et al. 2015

Cell Cycle

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Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and E2F1 target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy.

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Initial Genomics of the Human Nucleolus

Cited by 345 publications

References 51 publications

Subnuclear relocalization and silencing of a chromosomal region by an ectopic ribosomal DNA repeat

Subnuclear relocalization and silencing of a chromosomal region by an ectopic ribosomal DNA repeat

Functional redundancy in the nuclear compartmentalization of the late-replicating genome

Nucleolar repression facilitates initiation and maintenance of senescence

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