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Chromatin‐associated noncoding RNAs in development and inheritance

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Noncoding RNAs (ncRNAs) have emerged as crucial players in chromatin regulation. Their diversity allows them to partake in the regulation of numerous cellular processes across species. During development, long and short ncRNAs act in conjunction with each other where long ncRNAs (lncRNAs) are best understood in establishing appropriate gene expression patterns, while short ncRNAs (sRNAs) are known to establish constitutive heterochromatin and suppress mobile elements. Additionally, increasing evidence demonstrates roles of sRNAs in several typically lncRNA‐mediated processes such as dosage compensation, indicating a complex regulatory network of noncoding RNAs. Together, various ncRNAs establish many mitotically heritable epigenetic marks during development. Additionally, they participate in mechanisms that regulate maintenance of these epigenetic marks during the lifespan of the organism. Interestingly, some epigenetic traits are transmitted to the next generation(s) via paramutations or transgenerational inheritance mediated by sRNAs. In this review, we give an overview of the various functions and regulations of ncRNAs and the mechanisms they employ in the establishment and maintenance of epigenetic marks and multi‐generational transmission of epigenetic traits. WIREs RNA 2017, 8:e1435. doi: 10.1002/wrna.1435 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Development
Diverse roles of chromatin‐associated noncoding RNAs. Chromatin‐associated noncoding RNAs are involved in a variety of developmental processes such as formation of heterochromatin, dosage compensation, genomic imprinting, and pattern formation. They are also involved in the maintenance of epigenetic identity of chromatin during the cell cycle. In addition, they mediate transgenerational epigenetic inheritance through the germline.
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Transcription as a regulatory mechanism to centromeric chromatin during mitosis. (a) Schematic of a mitotic chromosome and magnification of centromeric chromatin. It is important to note that the precise higher order structure of centromeres is not known yet and the depicted structure is a speculative model. (b) In human cells, RNA polymerase II transcription is used as a transport mechanism to bring shugoshin (Sgo1) to the inner centromere, which is required for stabilization of centromeric cohesion. (c) In Xenopus, active mitotic transcription facilitates binding and activity of the CPC component Aurora‐B, which regulates mitotic progress via its kinase activity. (d) sRNAs originating from a retroelement disrupts CENP‐A localization in wallabies. In rice, CentO satellite repeats give rise to siRNAs, which are hypothesized to contribute to RNAi‐mediated chromatin modifications at the centromere. (e) In Drosophila and mammals, the generation of centromeric transcripts is required for the recruitment of specific centromeric factors such as Cenp‐C and Cenp‐A. This figure combines findings from different species as indicated.
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RNA‐mediated mechanisms of the re‐establishment of chromatin states after DNA replication. (a) Completion of DNA replication by the leading strand DNA polymerase (Pol epsilon, blue) requires clearance of RNA polymerases ahead of the replication fork. This can be facilitated by RNA processing events, such as siRNA generation in yeast. (e) This, in turn, promotes the formation of heterochromatin marks via RNAi‐mediated transcriptional gene silencing (TGS), which requires active RNA polymerase and RNA processing factors (RITS) for the generation of siRNAs. RNA polymerase II is regulated by the catalytic Pol epsilon subunit Cdc20 in yeast, coupling DNA replication, transcription and RNA‐mediated heterochromatin assembly. (b)–(c) Binding and eviction of replication‐independent HP1 to H3K9 methylation sites (green) are regulated by heterochromatic transcription in different species. (d) In mouse, initial HP1‐binding during replication is CAF‐1‐mediated and therefore connected to PCNA, which functions as a scaffold for several chromatin ‘readers’ and ‘writers’. Among these factors are histone methyltransferases, HP1, and methyl binding proteins (MBD), which are recruited by CAF‐1 to PCNA. (e) Human DNA methyltransferase DNMT1 is tethered to the replication fork by PCNA to re‐establish DNA methylation on hemi‐methylated strands. DNMT1 recruits further MBDs to strengthen chromatin states. The recruitment and activity of DNMT1 is regulated by a number of different lncRNAs. This figure combines findings from different species as labeled in the cartoon.
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Mechanisms of lncRNA‐mediated HOX gene regulation in Drosophila and mammals. (a) In Drosophila, iab‐8 lncRNA originates from the intergenic region between the genes abd‐A and Abd‐B and suppresses abd‐A by two mechanisms: (1) by miRNA production and (2) by transcriptional repression. iab‐4 lncRNA is produced from the antisense strand, but its function is not described in this review for simplicity. (b) In mammals, HOTTIP lncRNA is expressed from the 5′ end of the HOXA cluster. In humans, it binds WDR5 and therefore targets the Trx/MLL complex to the HOXA locus via preexisting chromosomal loops. This results in H3K4me3 accumulation. (c) HOTAIR transcript originates from the HOXC cluster and recruits PRC2 and coREST/REST complex in trans to the HOXD cluster genes as well as other genomic loci (not represented here). The PRC2 complex establishes H3K27me3 (transcription‐repressing mark) while the coREST/REST complex removes H3K4me2 (transcription‐activating mark). HOX clusters are not drawn to scale.
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Development
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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