lncRNA-Induced Spread of Polycomb Controlled by Genome Architecture, RNA Abundance, and CpG Island DNA

Schertzer, Megan D.; Braceros, Keean C. A.; Starmer, Joshua; Cherney, Rachel E; Lee, David M.; Salazar, Gabriela; Justice, Megan; Bischoff, Steve; Cowley, Dale O.; Ariel, Pablo; Zylka, Mark J.; Dowen, Jill M.; Magnuson, Terry; Calabrese, J. Mauro

doi:10.1016/j.molcel.2019.05.028

Cited by 115 publications

(247 citation statements)

References 79 publications

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“…The authors found that chromosome folding brought distal regions into close proximity of the transcribed lncRNA on the paternal allele [51], consistent with allelic differences in folding of the Airn/Igf2r locus seen in vivo [45]. CpG islands, in particular, enabled PRC targeting and spreading along the silenced paternal alleles within these imprinted domains [51]. However, the 3D folding of these regions and the proportion of polycomb-bound CpG islands were similar between embryonic stem cells and trophoblast stem cells.…”

Section: Imprinted Gene Clustersmentioning

confidence: 72%

“…A targeted deletion of the entire Airn gene indicated that the Airn lncRNA, rather than its genomic features, was essential for allelic silencing of nonoverlapped genes on the paternal allele [45]. To understand how lncRNAs could target such large genomic regions, the roles of chromosome folding, lncRNA abundance, and CpG islands in the targeting of Airn and Kcnq1ot1 lncRNAs was assessed in trophoblast stem cells [51]. The authors found that chromosome folding brought distal regions into close proximity of the transcribed lncRNA on the paternal allele [51], consistent with allelic differences in folding of the Airn/Igf2r locus seen in vivo [45].…”

Section: Imprinted Gene Clustersmentioning

confidence: 99%

“…To understand how lncRNAs could target such large genomic regions, the roles of chromosome folding, lncRNA abundance, and CpG islands in the targeting of Airn and Kcnq1ot1 lncRNAs was assessed in trophoblast stem cells [51]. The authors found that chromosome folding brought distal regions into close proximity of the transcribed lncRNA on the paternal allele [51], consistent with allelic differences in folding of the Airn/Igf2r locus seen in vivo [45]. CpG islands, in particular, enabled PRC targeting and spreading along the silenced paternal alleles within these imprinted domains [51].…”

Section: Imprinted Gene Clustersmentioning

confidence: 99%

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Placental imprinting: Emerging mechanisms and functions

Hanna

2020

PLoS Genet

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As the maternal-foetal interface, the placenta is essential for the establishment and progression of healthy pregnancy, regulating both foetal growth and maternal adaptation to pregnancy. The evolution and functional importance of genomic imprinting are inextricably linked to mammalian placentation. Recent technological advances in mapping and manipulating the epigenome in embryogenesis in mouse models have revealed novel mechanisms regulating genomic imprinting in placental trophoblast, the physiological implications of which are only just beginning to be explored. This review will highlight important recent discoveries and exciting new directions in the study of placental imprinting.

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Section: Imprinted Gene Clustersmentioning

confidence: 72%

Section: Imprinted Gene Clustersmentioning

confidence: 99%

Section: Imprinted Gene Clustersmentioning

confidence: 99%

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Placental imprinting: Emerging mechanisms and functions

Hanna

2020

PLoS Genet

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“…As exemplified by Xist, cis-acting RNAs may also function as negative regulators of neighboring gene expression. Repression in cis commonly underlies regulation of imprinted loci associated with positionally conserved lncRNAs-as for the example of Kcnq1ot1 and other lncRNAs, such as Airn and H19 (Barlow and Bartolomei, 2014;Schertzer et al, 2019). The large transcriptional burst size of Kcnq1ot1 and a transcript length of almost 100 kb, which requires an estimated half an hour to complete transcription, likely contribute to the generation of micrometer-large Kcnq1ot1 RNA clouds ( Figure 1C).…”

Section: Positional Conservation Of Cis-regulatory Rnas and Target Genesmentioning

confidence: 99%

“…The large transcriptional burst size of Kcnq1ot1 and a transcript length of almost 100 kb, which requires an estimated half an hour to complete transcription, likely contribute to the generation of micrometer-large Kcnq1ot1 RNA clouds ( Figure 1C). Such tethered RNA sponges efficiently recruit polycomb repressive complexes to silence neighboring genes allele-specifically over megabase distances (Murakami et al, 2007;Mohammad et al, 2008;Redrup et al, 2009;Larsson et al, 2019;Schertzer et al, 2019). RNA has been found as a key determinant for the association of Polycomb repressive complex 2 (PRC2) with chromatin.…”

Section: Positional Conservation Of Cis-regulatory Rnas and Target Genesmentioning

confidence: 99%

RNA, Genome Output and Input

2020

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RNA, the transcriptional output of genomes, not only templates protein synthesis or directly engages in catalytic functions, but can feed back to the genome and serve as regulatory input for gene expression. Transcripts affecting the RNA abundance of other genes act by mechanisms similar to and in concert with protein factors that control transcription. Through recruitment or blocking of activating and silencing complexes to specific genomic loci, RNA and protein factors can favor transcription or lower the local gene expression potential. Most regulatory proteins enter nuclei from all directions to start the search for increased affinity to specific DNA sequences or to other proteins nearby genuine gene targets. In contrast, RNAs emerge from spatial point sources within nuclei, their encoding genes. A transcriptional burst can result in the local appearance of multiple nascent RNA copies at once, in turn increasing local nucleic acid density and RNA motif abundance before diffusion into the nuclear neighborhood. The confined initial localization of regulatory RNAs causing accumulation of protein co-factors raises the intriguing possibility that target specificity of non-coding, and probably coding, RNAs is achieved through gene/RNA positioning and spatial proximity to regulated genomic regions. Here we review examples of positional cis conservation of regulatory RNAs with respect to target genes, spatial proximity of enhancer RNAs to promoters through DNA looping and RNA-mediated formation of membrane-less structures to control chromatin structure and expression. We speculate that linear and spatial proximity between regulatory RNA-encoding genes and gene targets could possibly ease the evolutionary pressure on maintaining regulatory RNA sequence conservation.

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