Architectural RNA is required for heterochromatin organization

Thakur, Jitendra; He, Fang; Llagas, Trizia; Henikoff, Steven

doi:10.1101/784835

Cited by 24 publications

(27 citation statements)

References 58 publications

(70 reference statements)

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“…We find that EZH2 occupancy, specifically at sites mediated by RNA binding, is essential in establishment of long-range genomic contacts and spreading of H3K27me3, potentially connecting widely separated chromatin regions as a "genomic wormhole" (Figure 4C). PRC2 binds thousands of RNAs on chromatin 32,33,50 and inhibition of EZH2-RNA interactions results in globally reduced EZH2 occupancy, altered H3K27me3 modification, and differentiation defects 15,51 .…”

Section: Discussionmentioning

confidence: 99%

Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

Kraft

Yost

Murphy

et al. 2020

Preprint

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SUMMARYPolycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction1-5. This process is essential for embryonic stem cell (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spread of H3K27me3 on the linear genome6. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear7-10. Here, we apply H3K27me3 HiChIP11-13, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture14 to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells7-10. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such as Hmx1, Wnt6 and Hoxa. Genetic deletion of H3K27me3 loop anchors revealed a coupling of Polycomb-associated genome architecture and H3K27me3 deposition evidenced by disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. Further, we find that global alterations in PRC2 occupancy resulting from an EZH2 mutant15 selectively deficient in RNA binding is accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 acts as a “genomic wormhole”, using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Additionally, developmental gene loci have novel roles in Polycomb spreading, emerging as important architectural elements of the epigenome.

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Section: Discussionmentioning

confidence: 99%

Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

Kraft

Yost

Murphy

et al. 2020

Preprint

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“…Similarly, defects in RNA decapping and degradation in cells lacking Caf1, a member of the Cccr4-Not complex, provoke transcriptional activation of subtelomeric regions and a decrease in H3K9me2 at CH loci (Bronner et al, 2017). Depletion of components of the Cccr4-Not complex also cause derepression of transposons in Drosophila and C. elegans (Fischer et al, 2013;Morgunova et al, 2015;Kordyukova et al, 2020) and RNAseA treatment alters heterochromatin stability and localization in mice (Thakur et al, 2019). Thus, RNA-mediated regulation might be a conserved mechanism to maintain heterochromatin stability.…”

Section: Heterochromatin Types and Establishmentmentioning

confidence: 99%

Heterochromatin as an Important Driver of Genome Organization

Penagos-Puig

Furlan-Magaril

2020

Front. Cell Dev. Biol.

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Heterochromatin is a constituent of eukaryotic genomes with functions spanning from gene expression silencing to constraining DNA replication and repair. Inside the nucleus, heterochromatin segregates spatially from euchromatin and is localized preferentially toward the nuclear periphery and surrounding the nucleolus. Despite being an abundant nuclear compartment, little is known about how heterochromatin regulates and participates in the mechanisms driving genome organization. Here, we review pioneer and recent evidence that explores the functional role of heterochromatin in the formation of distinct chromatin compartments and how failure of the molecular mechanisms forming heterochromatin leads to disarray of genome conformation and disease.

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“…Cell permeabilization with detergents renders chromatin modifying enzymes inactivate. Upon in situ RNA depletion by RNase A treatment, histones remain stably bound to DNA in the nucleosomes suggesting that the primary chromatin structure remains unaffected by RNase A treatment [39]. However, the higher order chromatin structure may be affected by the loss of RNA.…”

Section: Evidence For Structural Roles Of Rna In Chromatin Organizationmentioning

confidence: 99%

Architectural RNA in chromatin organization

Thakur

Henikoff

2020

Biochemical Society Transactions

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RNA plays a well-established architectural role in the formation of membraneless interchromatin nuclear bodies. However, a less well-known role of RNA is in organizing chromatin, whereby specific RNAs have been found to recruit chromatin modifier proteins. Whether or not RNA can act as an architectural molecule for chromatin remains unclear, partly because dissecting the architectural role of RNA from its regulatory role remains challenging. Studies that have addressed RNA's architectural role in chromatin organization rely on in situ RNA depletion using Ribonuclease A (RNase A) and suggest that RNA plays a major direct architectural role in chromatin organization. In this review, we will discuss these findings, candidate chromatin architectural long non-coding RNAs and possible mechanisms by which RNA, along with RNA binding proteins might be mediating chromatin organization.

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Architectural RNA is required for heterochromatin organization

Cited by 24 publications

References 58 publications

Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

Heterochromatin as an Important Driver of Genome Organization

Architectural RNA in chromatin organization

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