The redundancy of the mammalian heterochromatic compartment

Politz, Joan C. Ritland; Scalzo, David; Groudine, Mark

doi:10.1016/j.gde.2015.10.007

Cited by 40 publications

(40 citation statements)

References 77 publications

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“…Nucleoli are non-membrane-bound organelles within the nucleus. Not only are these sites of synthesis and assembly of ribosome components, but the periphery of these organelles plays an important role in higher-order chromosome localization (49,57). Specifically, the nucleolar periphery houses a subset of the cellular heterochromatin, which exchanges dynamically with lamina-associated heterochromatin (50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

“…The perinucleolar space is a subset of the heterochromatic compartment; another frequent location for heterochromatin is at the nuclear periphery, adjacent to the nuclear lamina (49). Accordingly, the Xi chromosome is usually localized to one of these two preferred locations (24).…”

mentioning

confidence: 99%

“…Accordingly, the Xi chromosome is usually localized to one of these two preferred locations (24). However, heterochromatic sequences can dynamically relocalize from nucleoli to the periphery, either during cell division or upon perturbation of the nucleolus by use of actinomycin (49)(50)(51)(52). Because Ki-67 depletion affected heterochromatic marks only on Xi chromosomes away from the nuclear periphery ( Fig.…”

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confidence: 99%

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Ki-67 Contributes to Normal Cell Cycle Progression and Inactive X Heterochromatin in p21 Checkpoint-Proficient Human Cells

Sun

Bizhanova

Matheson

et al. 2017

Molecular and Cellular Biology

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The Ki-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, and hTERT-BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by codepletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of the cell cycle inhibitor p21. Notably, induction of p21 upon depletion of Ki-67 was a consistent hallmark of cell types in which transcription and cell cycle distribution were sensitive to Ki-67; these responses were absent in cells that did not induce p21. Furthermore, upon Ki-67 depletion, a subset of inactive X (Xi) chromosomes in female hTERT-RPE1 cells displayed several features of compromised heterochromatin maintenance, including decreased H3K27me3 and H4K20me1 labeling. These chromatin alterations were limited to Xi chromosomes localized away from the nuclear lamina and were not observed in checkpoint-deficient 293T cells. Altogether, our results indicate that Ki-67 integrates normal S-phase progression and Xi heterochromatin maintenance in p21 checkpoint-proficient human cells.KEYWORDS cell cycle, heterochromatin K i-67 was first identified via an antibody raised against Hodgkin's lymphoma cell nuclei (1). Because Ki-67 is generally expressed strongly in proliferating cells and poorly in quiescent cells (2), anti-Ki-67 antibodies are frequently used to detect proliferative cells in clinical studies (3, 4). In interphase cells, Ki-67 primarily localizes to the nucleolus (5-7), whereas during mitosis, it coats the chromosomes (8-10). In the past few years, several studies have greatly increased our understanding of Ki-67 function. This is particularly true for its mitotic roles. Specifically, Ki-67 is required for formation of the mitotic perichromosomal layer (11, 12), a proteinaceous sheath that coats mitotic chromosomes (13,14). In this layer, Ki-67's large size and highly positively charged amino acid composition keep individual mitotic chromosomes dispersed rather than aggregated upon nuclear envelope disassembly, thereby ensuring normal kinetics of anaphase progression (15). At anaphase onset, Ki-67 binds protein phosphatase 1␥ (PP1␥) to form a holoenzyme (16) important for targeting substrates that must be dephosphorylated during mitotic exit (10). In contrast to its structural role on the

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Ki-67 Contributes to Normal Cell Cycle Progression and Inactive X Heterochromatin in p21 Checkpoint-Proficient Human Cells

Sun

Bizhanova

Matheson

et al. 2017

Molecular and Cellular Biology

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“…Constitutive heterochromatin tends to associate, forming chromocenters that are easily visible by light microscopy as they stain heavily [Schmid et al, 1975;Mayfield and Ellison, 1975]. Heterochromatin plays important roles in global genome organization [Politz et al, 2015] and in meiosis by shaping relatively stable unions between different bivalents . In spermatocytes, constitutive heterochromatin forms one or more condensed chromocenters that appear as clusters of chromatin denser than the otha b Fig.…”

Section: The Constitutive Heterochromatinmentioning

confidence: 99%

Nuclear Architecture of Mouse Spermatocytes: Chromosome Topology, Heterochromatin, and Nucleolus

Berríos

2017

Cytogenet Genome Res

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The nuclear organization of spermatocytes in meiotic prophase I is primarily determined by the synaptic organization of the bivalents that are bound by their telomeres to the nuclear envelope and described as arc-shaped trajectories through the 3D nuclear space. However, over this basic meiotic organization, a spermatocyte nuclear architecture arises that is based on higher-ordered patterns of spatial associations among chromosomal domains from different bivalents that are conditioned by the individual characteristics of chromosomes and the opportunity for interactions between their domains. Consequently, the nuclear architecture is species-specific and prone to modification by chromosomal rearrangements. This model is valid for the localization of any chromosomal domain in the meiotic prophase nucleus. However, constitutive heterochromatin plays a leading role in shaping nuclear territories. Thus, the nuclear localization of nucleoli depends on the position of NORs in nucleolar bivalents, but the association among nucleolar chromosomes mainly depends on the presence of constitutive heterochromatin that does not affect the expression of the ribosomal genes. Constitutive heterochromatin and nucleoli form complex nuclear territories whose distribution in the nuclear space is nonrandom, supporting the hypothesis regarding the existence of a species-specific nuclear architecture in first meiotic prophase spermatocytes.

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“…It has become clear that chromatin compaction is affected by many factors including DNA sequence, length of linker DNA, the use of histone variants, and epigenetic modifications of chromatin components [18,20,21]. Heterochromatin is also maintained by many heterochromatin-associated proteins such as heterochromatin protein 1 (HP1), methyltransferase suppressor of variegation 3-9 (SUV39), and histone deacetyltransferases (HDACs) [22,23].…”

Section: Heterochromatin Versus Euchromatinmentioning

confidence: 99%

Buried territories: heterochromatic response to DNA double-strand breaks

Feng¹,

Xiang²,

Kong³

et al. 2016

ABBS

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Cellular response to DNA double-strand breaks (DSBs), the most deleterious type of DNA damage, is highly influenced by higher-order chromatin structure in eukaryotic cells. Compared with euchromatin, the compacted structure of heterochromatin not only protects heterochromatic DNA from damage, but also adds an extra layer of control over the response to DSBs occurring in heterochromatin. One key step in this response is the decondensation of heterochromatin structure. This decondensation process facilitates the DNA damage signaling and promotes proper heterochromatic DSB repair, thus helping to prevent instability of heterochromatic regions of genomes. This review will focus on the functions of the ataxia telangiectasia mutated (ATM) signaling cascade involving ATM, heterochromatin protein 1 (HP1), Krüppel-associated box (KRAB)-associated protein-1 (KAP-1), tat-interacting protein 60 (Tip60), and many other protein factors in DSB-induced decondensation of heterochromatin and subsequent repair of heterochromatic DSBs. As some subsets of DSBs may be repaired in heterochromatin independently of the ATM signaling, a possible repair model is also proposed for ATM-independent repair of these heterochromatic DSBs.

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The redundancy of the mammalian heterochromatic compartment

Cited by 40 publications

References 77 publications

Ki-67 Contributes to Normal Cell Cycle Progression and Inactive X Heterochromatin in p21 Checkpoint-Proficient Human Cells

Ki-67 Contributes to Normal Cell Cycle Progression and Inactive X Heterochromatin in p21 Checkpoint-Proficient Human Cells

Nuclear Architecture of Mouse Spermatocytes: Chromosome Topology, Heterochromatin, and Nucleolus

Buried territories: heterochromatic response to DNA double-strand breaks

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