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Roles of long noncoding RNAs in chromosome domains

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The cell nucleus is highly organized and functionally compartmentalized. Double‐stranded naked DNA is complexed with core histones and assembled into nucleosomes and chromatin, which are surrounded by nuclear domains composed of RNAs and proteins. Recently, three‐dimensional views of chromosome organization beyond the level of the nucleosome have been established and are composed of several layers of chromosome domains. Only a small portion of the human genome encodes proteins; the majority is pervasively transcribed into noncoding RNAs whose functions are under intensive investigation. Importantly, the questions of how nuclear retained noncoding RNAs play roles in orchestrating the chromatin structure that have been addressed. We discuss the novel noncoding RNA clusters, Eleanors, which are derived from a large chromatin domain. They accumulate at the site of their own transcription to form RNA clouds in the nucleus, and they activate gene expression in the chromatin domain. Noncoding RNAs have emerging roles in genome regulation that are integrated into the spatial organization of chromatin and the nucleus. WIREs RNA 2017, 8:e1384. doi: 10.1002/wrna.1384 This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease
Hierarchical organization of chromosomal domains in the nucleus. Chromosomes are intricately folded into multiple layers. Chromosome/chromatin domains are illustrated in order of scale: larger (top) to smaller (bottom). At the top, each chromosome, denoted with a different color, occupies a specific space known as a chromosome territory (CTs). Certain parts of a chromosome are associated with subnuclear structures, including the nucleolus and the nuclear lamina, and form nucleolus‐associated chromatin domains (NADs) and lamina‐associated domains (LADs), respectively. A and B compartments contain large chromatin domains, which are transcriptionally active and inactive, respectively (middle). A and B compartments are composed of topologically associating domains (TADs), which are physically packaged linear units of chromatin (middle). Within TADs, various types of loops, including one allowing cell‐type‐specific interactions of promoters and distal regulatory elements, play a central role in gene expression regulation (bottom).
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Large chromatin domain defined by the production of Eleanor ncRNAs in breast cancer. (a) Schematic view of the chromatin domain containing the ESR1 locus on human chromosome 6. The domain is demarcated by a high level of Pol II binding and active histone marks (H3K36me3) (black and grey bars) and by transcription of Eleanors (red bar) in breast cancer cells. The domain contains four coregulated genes: ESR1, C6orf97, C6orf211, and C6orf96. (b) Models for the Eleanor chromatin domain in ER+ breast cancer (left) and endocrine therapy‐resistant breast cancer (LTED, right). Eleanor RNA FISH (red signals) shows RNA clouds (right). u‐Eleanor and intragenic Eleanors are actively transcribed throughout the chromatin domain, stably retained at the site of their own transcription, and maintain the active chromatin domain in LTED cells.
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LncRNAs as organizers of nuclear structures. (a) Xist RNA is transcribed from one of the X chromosomes and spreads to the proximal region where it recruits repressive complexes to establish and maintain the inactive state. Xist covers the entire X chromosome, leading to a compacted inactive chromosomal domain, which is further localized to the periphery of the nucleus. (b) Firre RNA is retained at its transcription site and recruits specific genes located on different chromosomes through hnRNPU. It functions as a platform for trans‐chromosomal associations and coactivation of the genes. (c) NEAT1 RNA serves as a seed for a nuclear body, the paraspeckle, in cooperation with its component proteins. (d) TUG1 and MALAT1 RNAs promote the relocation of growth control genes in response to growth signal by selectively interacting with methylated and unmethylated Pc2 on gene promoters. (e) SRA RNA interacts with p68 to form a complex with CTCF and cohesin, and contributes to the enhancer‐blocking activity via a long‐range chromosomal interaction.
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Contribution of interspersed repeats in diverse transcripts. Human Alu and mouse B2 RNAs can inhibit Pol II transcription by direct interactions.
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ncRNAs transcribed from enhancer elements mediate gene activation. Enhancer RNAs, together with transcriptional mediator proteins, play a role in interactions between the enhancer sequence and its target promoter, resulting in local chromosome loop formation.
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LncRNAs regulate transcription through a variety of mechanisms. (a–c) LncRNAs mediate epigenetic changes by recruiting chromatin modulators to specific loci. Xist functions in cis on the Xi chromosome (a), HOTAIR is synthesized on chromosome 12 and exerts its function in trans on the HOXD cluster on chromosome 2 (b), HOTTIP functions on the distantly located HOXA locus via loop formation (c), and TERRA is localize to telomeres to confer a variety of functions on telomeres (d).
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Disease

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