RNA promotes the formation of spatial compartments in the nucleus

Quinodoz, Sofia A.; Jachowicz, Joanna W.; Bhat, Prashant; Ollikainen, Noah; Banerjee, Abhik; Goronzy, Isabel N.; Blanco, Mario R.; Chovanec, Peter; Chow, Amy; Markaki, Yolanda; Thai, Jasmine; Plath, Kathrin; Guttman, Mitchell

doi:10.1016/j.cell.2021.10.014

Cited by 269 publications

(204 citation statements)

References 103 publications

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“…In this manuscript we utilize a series of 9 transgene deletions that span the XIST cDNA to determine the regions of XIST critical for silencing and chromatin remodelling. Growing evidence from research groups studying XIST, including our own, have suggested that interactions between domains of XIST RNA (both intramolecular and intermolecular) are not only endemic [ 8 ] but essential to numerous functions of XIST including chromatin remodelling [ 13 , 24 ]. Deletions can not only remove domains of interacting proteins, but may also impact the RNA structure of the remaining RNA.…”

Section: Discussionmentioning

confidence: 99%

Multiple distinct domains of human XIST are required to coordinate gene silencing and subsequent heterochromatin formation

Dixon-McDougall

Brown

2022

Epigenetics & Chromatin

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Background Mammalian dosage compensation is achieved by the inactivation of one X chromosome in XX individuals. In eutheria this process is initiated early in development by the long non-coding RNA XIST. Studies of the initiation of silencing by XIST have focussed on mouse models, so the domains of XIST required to induce silencing in humans, and their relationship with domains required to establish heterochromatin remain to be determined. Methods We have previously established an inducible XIST cDNA in somatic cells and shown it can induce silencing and recruit heterochromatic features. We now assess a series of deletions across the transgene for the ability to induce silencing and integrate these results with time-course and chromatin-remodelling inhibitor treatments to follow the steps of XIST-induced silencing and heterochromatinization. Discussion We find that in addition to the previously reported necessity of the 5’ A repeat region for XIST-induced silencing, the 1 kb around the small F repeat region and a non-repetitive region at the 3’ end of the RNA are also required to silence genes. Silencing of genes up to 17 Mb from the XIST integration occurs within 2 days, while formation of a Cot-1 depleted domain is slower, and more dependent on the region encompassing Repeat F. The role of this region encompassing Repeat F in both the silencing of actively transcribed genes, the spread of H3K27me3 and the formation of a transcriptionally inert domain suggests a role in a pathway crucial for the spread of XIST across the chromatin to target distal regions of inactivation. Histone deacetylation requires only the A repeat region, with HDAC3 inhibition showing limited effect on silencing, but an impact on H3K27me3 recruitment, and as a result the recruitment of MacroH2A. Global HDAC inhibition impacted silencing in both a distance and dose-dependent fashion. The E repeat region was required for CIZ1 and H4K20me1 recruitment as well as H3K27me3; however, these appeared to act relatively independently. The H3K27me3 mark established by PRC2 integrated silencing and many of the heterochromatic features, while the PRC1 mark ubH2A appeared to be downstream of silencing in these human somatic cells.

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Section: Discussionmentioning

confidence: 99%

Multiple distinct domains of human XIST are required to coordinate gene silencing and subsequent heterochromatin formation

Dixon-McDougall

Brown

2022

Epigenetics & Chromatin

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“…This suggests that YTHDC1 may also help trigger the assembly of repressive H3K27me3, which was recently observed at a reporter gene that expressed m 6 A-modified long RNA [107]. Finally, Quinodoz et al found that minor and major satellite-derived RNAs cluster at HP1/H3K9me3-rich pericentromeric regions [32]. These RNAs were necessary to recruit HP1 clusters, suggesting that they may act similar to fission yeast nam lncRNAs to promote pericentromeric heterochromatin.…”

Section: Rna-mediated Chromatin Modificationsmentioning

confidence: 78%

“…Genome-wide approaches can also be used to propose regulatory functions via indirect means. Due to the shear abundance of available approaches, Table 1 represents an inexhaustive list of these methods that measure different biophysical properties of lncRNAs including RNA-DNA interactions [32][33][34][35][36], inter-RNA-RNA interactions [37][38][39][40], RNA-protein interactions [41][42][43][44][45] and RNA localization [46][47][48]. More comprehensive reviews elsewhere have been performed on methods that map complex RNA-chromatin interactions [49,50].…”

Section: Tools To Identify Long Regulatory Rnasmentioning

confidence: 99%

Long RNA-Mediated Chromatin Regulation in Fission Yeast and Mammals

Faber

2022

IJMS

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As part of a complex network of genome control, long regulatory RNAs exert significant influences on chromatin dynamics. Understanding how this occurs could illuminate new avenues for disease treatment and lead to new hypotheses that would advance gene regulatory research. Recent studies using the model fission yeast Schizosaccharomyces pombe (S. pombe) and powerful parallel sequencing technologies have provided many insights in this area. This review will give an overview of key findings in S. pombe that relate long RNAs to multiple levels of chromatin regulation: histone modifications, gene neighborhood regulation in cis and higher-order chromosomal ordering. Moreover, we discuss parallels recently found in mammals to help bridge the knowledge gap between the study systems.

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“…Recently, it has been shown that satellite-derived noncoding RNAs are localized in spatial proximity to centromeres and pericentromeres for their function ( 67 ). Similarly, several noncoding RNAs are localized to their site of transcription to form a hub, demarcating a nuclear compartment, for interchromosomal associations and gene regulatory functions.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, several noncoding RNAs are localized to their site of transcription to form a hub, demarcating a nuclear compartment, for interchromosomal associations and gene regulatory functions. However, perturbing histone Post-translational modifications (PTMs) is shown to affect the gene regulatory function of lncRNAs within their nuclear territory, although it does not affect the lncRNA’s localization at its transcriptional locus ( 67 ). It is possible that although PCAT2 binds histone H3, proper folding of the RNA and specific PTMs in the CENP-A protein might be critical for PCAT2 ’s association with CENP-A and co-chaperoning function.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic lncRNAs alter epigenetic memory at a fragile chromosomal site in human cancer cells

et al. 2022

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Chromosome instability is a critical event in cancer progression. Histone H3 variant CENP-A plays a fundamental role in defining centromere identity, structure, and function but is innately overexpressed in several types of solid cancers. In the cancer background, excess CENP-A is deposited ectopically on chromosome arms, including 8q24/ cMYC locus, by invading transcription-coupled H3.3 chaperone pathways. Up-regulation of lncRNAs in many cancers correlates with poor prognosis and recurrence in patients. We report that transcription of 8q24-derived oncogenic lncRNAs plays an unanticipated role in altering the 8q24 chromatin landscape by H3.3 chaperone–mediated deposition of CENP-A–associated complexes. Furthermore, a transgene cassette carrying specific 8q24-derived lncRNA integrated into a naïve chromosome locus recruits CENP-A to the new location in a cis-acting manner. These data provide a plausible mechanistic link between locus-specific oncogenic lncRNAs, aberrant local chromatin structure, and the generation of new epigenetic memory at a fragile site in human cancer cells.

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RNA promotes the formation of spatial compartments in the nucleus

Cited by 269 publications

References 103 publications

Multiple distinct domains of human XIST are required to coordinate gene silencing and subsequent heterochromatin formation

Multiple distinct domains of human XIST are required to coordinate gene silencing and subsequent heterochromatin formation

Long RNA-Mediated Chromatin Regulation in Fission Yeast and Mammals

Oncogenic lncRNAs alter epigenetic memory at a fragile chromosomal site in human cancer cells

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