Phase separation and nucleosome compaction are governed by the same domain of Polycomb Repressive Complex 1

Plys, Aaron J.; Davis, Connor; Kim, Jongmin; Rizki, Gizem; Keenen, Madeline M.; Marr, Sharon K.; Kingston, Robert E.

doi:10.1101/467316

Cited by 12 publications

(18 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to previous epigenetic switching models, which only consider the dynamics of histone modification ( Dodd et al, 2007 ; Zhang et al, 2014 ), the methylation-compaction model we propose couples histone methylation to nucleosomal interactions. Consistent with this idea, both H3K27me3 and H3K9me2/3 can promote nucleosomal self-association though histone-tail interactions ( Gibson et al, 2019 ) or by recruiting protein complexes that self-associate to form phase-separated condensates ( Plys et al, 2018 ; Sanulli et al, 2019 ; Tatavosian et al, 2019 ; Wang et al, 2019 ). Importantly, in order for the activation times to be tunable, nucleosomes must retain some self-interaction affinity without H3K27me3, such that methylation promotes but is not strictly necessary for nucleosomal association.…”

Section: Discussionmentioning

confidence: 78%

Tunable, division-independent control of gene activation timing by a polycomb switch

et al. 2021

View full text Add to dashboard Cite

SUMMARY During development, progenitors often differentiate many cell generations after receiving signals. These delays must be robust yet tunable for precise population size control. Polycomb repressive mechanisms, involving histone H3 lysine-27 trimethylation (H3K27me3), restrain the expression of lineage-specifying genes in progenitors and may delay their activation and ensuing differentiation. Here, we elucidate an epigenetic switch controlling the T cell commitment gene Bcl11b that holds its locus in a heritable inactive state for multiple cell generations before activation. Integrating experiments and modeling, we identify a mechanism where H3K27me3 levels at Bcl11b , regulated by methyltransferase and demethylase activities, set the time delay at which the locus switches from a compacted, silent state to an extended, active state. This activation delay robustly spans many cell generations, is tunable by chromatin modifiers and transcription factors, and is independent of cell division. With their regulatory flexibility, such timed epigenetic switches may broadly control timing in development.

show abstract

Section: Discussionmentioning

confidence: 78%

Tunable, division-independent control of gene activation timing by a polycomb switch

et al. 2021

View full text Add to dashboard Cite

show abstract

“…As a consequence, Xist and its interacting partners might stabilize this structure, thereby establishing an epigenetic memory of the original A-compartment structure present at the time of X-inactivation, which is then maintained on the inactive X chromosome. The spatial separation between two types of heterochromatin on the inactive X, the Xist/Polycomb-rich A-like and the H3K9me-rich B-like heterochromatin, could be driven by liquidliquid phase separation (LLPS) mechanisms, which have been previously described for both Polycomb (Plys et al, 2019) and H3K9me2/3 domains (Larson et al, 2017;Strom et al, 2017). Indeed, Xist RNA recruits a multitude of factors involved in LLPS to the inactive X (Cerase et al, 2019) and Xist-deletion or depletion of Xist-associated LLPS factors like PRC1 and hnRNPK has been shown to significantly compromise the underlying Xi compartment structure (Wang et al, 2019).…”

Section: Compartmentalization Of the Inactive X-chromosomementioning

confidence: 92%

Chromosome Compartments on the Inactive X Guide TAD Formation Independently of Transcription during X-Reactivation

Bauer

Vidal

Zorita

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryA hallmark of chromosome organization is the partition into transcriptionally active A and repressed B compartments and into topologically associating domains (TADs). Both structures were regarded absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, we combine a tailor-made mouse iPSC-reprogramming system and high-resolution Hi-C to produce the first time-course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation. Contrary to previous observations, we uncover A/B-like compartments on the inactive X harboring multiple subcompartments. While partial X-reactivation initiates within a compartment rich in X-inactivation escapees, it then occurs rapidly along the chromosome, coinciding with acquisition of naive pluripotency, leading to downregulation of Xist. Importantly, we find that TAD formation precedes transcription, suggesting them to be causally independent. Instead, TADs form first within Xist-poor compartments, establishing Xist as common denominator, opposing both gene reactivation and TAD formation through separate mechanisms.Graphical Summary

show abstract

“…5c). In pluripotent cells, these PE-gene interactions are mediated by PcG complexes recruited to both oCGIs and pCGIs 8,9,82,83 and are likely to be dependent on the polymerization and/or phase separation properties of PRC1 [60][61][62]84 .…”

Section: Discussionmentioning

confidence: 99%

Orphan CpG islands boost the regulatory activity of poised enhancers and dictate the responsiveness of their target genes

Rada-Iglesias

2020

Preprint

View full text Add to dashboard Cite

ARTICLECpG islands (CGIs) represent a distinctive and widespread genetic feature of vertebrate genomes, being associated with ∼70% of all annotated gene promoters1. CGIs have been proposed to control transcription initiation by conferring nearby promoters with unique chromatin properties2–4. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance and mechanism of action are barely known5–7. Here we show that oCGIs are an essential component of poised enhancers (PEs)8, 9 that boost their long-range regulatory activity and dictate the responsiveness of their target genes. Using a CRISPR/Cas9 knock-in strategy in mESC, we introduced PEs with or without oCGIs within topological associating domains (TADs) harbouring genes with different types of promoters. By evaluating the chromatin, topological and regulatory properties of the engineered PEs, we uncover that, rather than increasing their local activation, oCGIs boost the physical and functional communication between PEs and distally located developmental genes. Furthermore, we demonstrate that developmental genes with CpG rich promoters are particularly responsive to PEs and that such responsiveness depends on the presence of oCGIs. Therefore, our work unveils a novel role for CGIs as genetic determinants of the compatibility between genes and enhancers, thus providing major insights into how developmental gene expression programs are deployed under both physiological and pathological conditions10–12.

show abstract

Phase separation and nucleosome compaction are governed by the same domain of Polycomb Repressive Complex 1

Cited by 12 publications

References 38 publications

Tunable, division-independent control of gene activation timing by a polycomb switch

Tunable, division-independent control of gene activation timing by a polycomb switch

Chromosome Compartments on the Inactive X Guide TAD Formation Independently of Transcription during X-Reactivation

Orphan CpG islands boost the regulatory activity of poised enhancers and dictate the responsiveness of their target genes

Contact Info

Product

Resources

About