Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing

Chen, Chun Kan; Blanco, Mario R.; Jackson, Constanza; Aznauryan, Erik; Ollikainen, Noah; Surka, Christine; Chow, Amy; Cerase, Andrea; McDonel, Patrick; Guttman, Mitchell

doi:10.1126/science.aae0047

Cited by 249 publications

(236 citation statements)

References 49 publications

(62 reference statements)

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“…Interestingly, Matrin3 has also been identified as a candidate Xist interactor (Chu et al 2015;Moindrot et al 2015). Further studies are nevertheless required to determine whether there is a direct interaction between CIZ1 and Xist RNA, specifically the E repeat region, and, at this stage, we cannot rule out that CIZ1 recognizes other Xist-interacting protein; for example, PTBP1 and PTBP2, recently shown to bind the E repeat region (Chen et al 2016).…”

Section: Discussionmentioning

confidence: 94%

The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory

et al. 2017

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The nuclear matrix protein Cip1-interacting zinc finger protein 1 (CIZ1) promotes DNA replication in association with cyclins and has been linked to adult and pediatric cancers. Here we show that CIZ1 is highly enriched on the inactive X chromosome (Xi) in mouse and human female cells and is retained by interaction with the RNA-dependent nuclear matrix. CIZ1 is recruited to Xi in response to expression of X inactive-specific transcript (Xist) RNA during the earliest stages of X inactivation in embryonic stem cells and is dependent on the C-terminal nuclear matrix anchor domain of CIZ1 and the E repeats of Xist. CIZ1-null mice, although viable, display fully penetrant female-specific lymphoproliferative disorder. Interestingly, in mouse embryonic fibroblast cells derived from CIZ1-null embryos, Xist RNA localization is disrupted, being highly dispersed through the nucleoplasm rather than focal. Focal localization is reinstated following re-expression of CIZ1. Focal localization of Xist RNA is also disrupted in activated B and T cells isolated from CIZ1-null animals, suggesting a possible explanation for female-specific lymphoproliferative disorder. Together, these findings suggest that CIZ1 has an essential role in anchoring Xist to the nuclear matrix in specific somatic lineages.

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Section: Discussionmentioning

confidence: 94%

The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory

et al. 2017

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“…Recent data show that the nuclear lamina localization mediated by the interaction between XIST and the lamina B receptor facilitates the spreading of XIST on the Xi chromosome, which in turn contributes to transcriptional silencing (62). This raises the question of whether there are specific protein factors that contribute to the association of the Xi chromosome with the nucleolus in addition to the lncRNAs XIST and Firre (24,60).…”

Section: Discussionmentioning

confidence: 99%

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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“…Autoimmune sera containing antibodies against the Barr body have been identified, although at low frequency [132]. Antibodies to the Lamin B Receptor (LBR), an Xist-interacting protein [133], are seen with the female-biased, autoimmune disorder primary biliary cirrhosis [134], which interestingly often shows increased loss of the inactive X (or Y chromosome in rarer male cases). Mutations in LBR have been identified in Reynolds syndrome, which comprised the related, female-biased, autoimmune disorders scleroderma and primary biliary cirrhosis.…”

Section: (A) Systemic Lupus Erythematosusmentioning

confidence: 99%

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

Carrel

Brown

2017

Phil. Trans. R. Soc. B

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A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation.

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Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing

Cited by 249 publications

References 49 publications

The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory

The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory

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

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

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