PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome

Arruda, Nicole L.; Bryan, Audra F.; Dowen, Jill M.

doi:10.1186/s13072-022-00463-6

Cited by 2 publications

(4 citation statements)

References 72 publications

(152 reference statements)

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“…Based on this classification, our transcriptome analysis revealed that PRC1/PRC2 target gene expression was significantly increased in both Pds5a GT KO ESCs and Pds5a KO ESCs (Fig. 2c, d ), in agreement with a recent report 50 . Consistent with derepression of PRC1/PRC2 target genes, Gene Ontology (GO) analysis of upregulated genes revealed terms related to developmental processes such as neurogenesis and pattern specification (Fig.…”

Section: Resultssupporting

confidence: 92%

“…As expected, PDS5A showed extensive overlap with RAD21 and CTCF (Supplementary Fig. 4a–d ) 50 , 58 , 59 . In contrast, PDS5A was absent from Polycomb target genes, suggesting that PDS5A indirectly promotes silencing of PRC1/PRC2 target genes (Supplementary Fig.…”

Section: Resultssupporting

confidence: 82%

“…Given cohesin's essential role in sister chromatid cohesion, deletion of cohesin subunits frequently impairs cell proliferation, hampering the analysis of its precise function in gene regulation [46][47][48] . Although most cohesin proteins are essential for ESC viability [46][47][48] , both PDS5A and STAG2 have paralogs with redundant but not identical functions that are sufficient to maintain self-renewal and proliferation 45,50 . Indeed, Pds5a KO ESC lines displayed characteristically dense colonies that could be stably maintained in culture, similar to wild-type ESCs (Supplementary Fig.…”

Section: Loss Of Pds5a Results In De-repression Of Endogenous Prc1/ P...mentioning

confidence: 99%

“…For example, a genetic screen for dominant suppressors of Polycomb-dependent silencing in Drosophila revealed several mutants in the wapl gene 64 . In mammalian cells, PDS5A and PDS5B are required for Polycomb-dependent silencing 50 , and Pds5a KO mice exhibit developmental abnormalities, including skeletal malformations 65 , that resemble the patterning defects of Polycomb mutant mice 24 , 66 , 67 . Our results provide a mechanistic explanation linking changes in 3D genome architecture to defects in Polycomb-dependent gene silencing.…”

Section: Discussionmentioning

confidence: 99%

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Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops

Bsteh,

Moussa,

Michlits

et al. 2023

Nat Commun

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Polycomb Repressive Complexes 1 and 2 (PRC1, PRC2) are conserved epigenetic regulators that promote transcriptional gene silencing. PRC1 and PRC2 converge on shared targets, catalyzing repressive histone modifications. Additionally, a subset of PRC1/PRC2 targets engage in long-range interactions whose functions in gene silencing are poorly understood. Using a CRISPR screen in mouse embryonic stem cells, we found that the cohesin regulator PDS5A links transcriptional silencing by Polycomb and 3D genome organization. PDS5A deletion impairs cohesin unloading and results in derepression of a subset of endogenous PRC1/PRC2 target genes. Importantly, derepression is not linked to loss of Polycomb chromatin domains. Instead, PDS5A removal causes aberrant cohesin activity leading to ectopic insulation sites, which disrupt the formation of ultra-long Polycomb loops. We show that these loops are important for robust silencing at a subset of PRC1/PRC2 target genes and that maintenance of cohesin-dependent genome architecture is critical for Polycomb regulation.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 82%

Section: Loss Of Pds5a Results In De-repression Of Endogenous Prc1/ P...mentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops

Bsteh,

Moussa,

Michlits

et al. 2023

Nat Commun

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The physical chemistry of interphase loop extrusion

Tortora,

Fudenberg

2024

Preprint

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Loop extrusion constitutes a universal mechanism of genome organization, whereby structural maintenance of chromosomes (SMC) protein complexes load onto the chromatin fiber and generate DNA loops of increasingly-larger sizes until their eventual release. In mammalian interphase cells, loop extrusion is mediated by the cohesin complex, which is dynamically regulated by the interchange of multiple accessory proteins. Although these regulators bind the core cohesin complex only transiently, their disruption can dramatically alter cohesin dynamics, gene expression, chromosome morphology and contact patterns. Still, a theory of how cohesin regulators and their molecular interplay with the core complex modulate genome folding remains at large. Here we derive a model of cohesin loop extrusion from first principles, based onin vivomeasurements of the abundance and dynamics of cohesin regulators. We systematically evaluate potential chemical reaction networks that describe the association of cohesin with its regulators and with the chromatin fiber. Remarkably, experimental observations are consistent with only a single biochemical reaction cycle, which results in a unique minimal model that may be fully parameterized by quantitative protein measurements. We demonstrate how distinct roles for cohesin regulators emerge simply from the structure of the reaction network, and how their dynamic exchange can regulate loop extrusion kinetics over time-scales that far exceed their own chromatin residence times. By embedding our cohesin biochemical reaction network within biophysical chromatin simulations, we evidence how variations in regulatory protein abundance can alter chromatin architecture across multiple length- and time-scales. Predictions from our model are corroborated by biophysical and biochemical assays, optical microscopy observations, and Hi-C conformation capture techniques. More broadly, our theoretical and numerical framework bridges the gap betweenin vitroobservations of extrusion motor dynamics at the molecular scale and their structural consequences at the genome-wide level.

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PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome

Cited by 2 publications

References 72 publications

Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops

Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops

The physical chemistry of interphase loop extrusion

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