The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism

Ruiten, Marjon S. van; Gent, Démi van; Cacciatore, Ángela Sedeño; Fauster, Astrid; Willems, Laureen; Hekkelman, Maarten L.; Hoekman, Liesbeth; Altelaar, Maarten; Haarhuis, Judith H.I.; Brummelkamp, Thijn R.; Wit, Elzo de; Rowland, Benjamin D.

doi:10.1038/s41594-022-00773-z

Cited by 37 publications

(35 citation statements)

References 45 publications

(68 reference statements)

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“…Our immunoprecipitation data confirm that human cohesin complexes bound to PDS5 do not interact with NIPBL, as suggested by results in yeast [ 31 ]. The competition of NIPBL and PDS5 for binding cohesin appears to be regulated by acetylation [ 51 , 27 ]. This acetylation, in turn, may occur preferentially at CTCF sites, as it is dramatically reduced in Ctcf KO MEFs [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…This explains why cohesin largely colocalizes with CTCF genome-wide [ 23 , 24 ]. The boundary and/or anchoring function of CTCF depends on its interaction with an interface formed by STAG and RAD21, which is the same that requires WAPL, but possibly also on PDS5 and ESCO1 [ 25 , 26 , 27 , 7 , 13 ]. Recent in vitro reconstitution of loop extrusion by cohesin has demonstrated the requirement for NIPBL to activate the SMC1/3 ATPase [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Contribution of variant subunits and associated factors to genome-wide distribution and dynamics of cohesin

Cuadrado

Giménez-Llorente

Koninck

et al. 2022

Epigenetics & Chromatin

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Background The cohesin complex organizes the genome-forming dynamic chromatin loops that impact on all DNA-mediated processes. There are two different cohesin complexes in vertebrate somatic cells, carrying the STAG1 or STAG2 subunit, and two versions of the regulatory subunit PDS5, PDS5A and PDS5B. Mice deficient for any of the variant subunits are embryonic lethal, which indicates that they are not functionally redundant. However, their specific behavior at the molecular level is not fully understood. Results The genome-wide distribution of cohesin provides important information with functional consequences. Here, we have characterized the distribution of cohesin subunits and regulators in mouse embryo fibroblasts (MEFs) either wild type or deficient for cohesin subunits and regulators by chromatin immunoprecipitation and deep sequencing. We identify non-CTCF cohesin-binding sites in addition to the commonly detected CTCF cohesin sites and show that cohesin-STAG2 is the preferred variant at these positions. Moreover, this complex has a more dynamic association with chromatin as judged by fluorescence recovery after photobleaching (FRAP), associates preferentially with WAPL and is more easily extracted from chromatin with salt than cohesin-STAG1. We observe that both PDS5A and PDS5B are exclusively located at cohesin-CTCF positions and that ablation of a single paralog has no noticeable consequences for cohesin distribution while double knocked out cells show decreased accumulation of cohesin at all its binding sites. With the exception of a fraction of cohesin positions in which we find binding of all regulators, including CTCF and WAPL, the presence of NIPBL and PDS5 is mutually exclusive, consistent with our immunoprecipitation analyses in mammalian cell extracts and previous results in yeast. Conclusion Our findings support the idea that non-CTCF cohesin-binding sites represent sites of cohesin loading or pausing and are preferentially occupied by the more dynamic cohesin-STAG2. PDS5 proteins redundantly contribute to arrest cohesin at CTCF sites, possibly by preventing binding of NIPBL, but are not essential for this arrest. These results add important insights towards understanding how cohesin regulates genome folding and the specific contributions of the different variants that coexist in the cell.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contribution of variant subunits and associated factors to genome-wide distribution and dynamics of cohesin

Cuadrado

Giménez-Llorente

Koninck

et al. 2022

Epigenetics & Chromatin

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“…These results suggest that all cohesin’s biological functions can be carried out by cohesin in a single acetylated state with ATPase activity either lower (smc3-K112R, K113R smc1-T1117W, or smc3-K113R smc1-D1164E) or higher (smc1-T1117I smc3-K113Q) that wild type. One possibility is that the ATPase and its biological functions are controlled by an additional regulatory protein like Pds5p (Bastié et al 2022; van Ruiten et al 2022). However, invoking redundancy avoids the question of what is the fitness advantage for the acetylation-dependent control of cohesin’s ATPase.…”

Section: Discussionmentioning

confidence: 99%

“…1A). A recent study suggested that Smc3p-K113 acetylation inhibited Scc2p binding to cohesin indirectly by stabilizing the binding of Pds5p, which then precluded Scc2p binding (Bastié et al 2022; van Ruiten et al 2022). However, a more direct mechanism was suggested by the observation that Scc2p stimulation of cohesin ATPase activity in vitro is drastically reduced by a mutation that mimics acetylation by substituting glutamine for K113 (K113Q) (Murayama and Uhlmann 2015).…”

Section: Introductionmentioning

confidence: 99%

A model for Scc2p Stimulation of Cohesin’s ATPase and its Inhibition by Acetylation of Smc3p

Boardman

Xiang

Chatterjee

et al. 2022

Preprint

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The evolutionarily conserved cohesin complex mediates sister chromatid cohesion and facilitates mitotic chromosome condensation, DNA repair, and transcription regulation. These biological functions require cohesin’s two ATPases, formed by the Smc1p and Smc3p subunits. Cohesin’s ATPase activity is stimulated by the Scc2p auxiliary factor. This stimulation is inhibited by Eco1p acetylation of Smc3p at an interface with Scc2p. It was unclear how cohesin’s ATPase activity is stimulated by Scc2p, or how acetylation inhibits Scc2p, given that the acetylation site is distal to cohesin’s ATPase active sites. Here, we identify mutations in budding yeast that suppressed the in vivo defects caused by Smc3p acetyl-mimic and acetyl-defective mutations. We provide compelling evidence that Scc2p activation of cohesin ATPase depends upon an interface between Scc2p and a region of Smc1p proximal to cohesin’s Smc3p ATPase active site. Furthermore, substitutions at this interface increase or decrease ATPase activity to overcome ATPase modulation by acetyl-mimic and - null mutations. Using these observations and a cryo-EM structure, we propose a model for regulating cohesin ATPase activity. We suggest that Scc2p binding to Smc1p causes a shift in adjacent Smc1p residues and ATP, stimulating the Smc3p ATPase. This stimulatory shift is inhibited through acetylation of the distal Scc2p-Smc3 interface.

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“…Cohesin, stimulated by NIPBL, acts as an adenosine triphosphate (ATP)dependent molecular motor extruding DNA and folding the genome into topologically associated domains (TADs) (10)(11)(12)(13). Removing either PDS5 or WAPL stabilizes cohesin binding to chromatin and can alter TAD structure in different ways (4,(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl ^+/− embryos

et al. 2022

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Cohesin rings interact with DNA and modulate the expression of thousands of genes. NIPBL loads cohesin onto chromosomes, and WAPL takes it off. Haploinsufficiency for NIPBL causes a developmental disorder, Cornelia de Lange syndrome (CdLS), that is modeled by Nipbl +/− mice. Mutations in WAPL have not been shown to cause disease or gene expression changes in mammals. Here, we show dysregulation of >1000 genes in Wapl Δ /+ embryonic mouse brain. The patterns of dysregulation are highly similar in Wapl and Nipbl heterozygotes, suggesting that Wapl mutations may also cause human disease. Since WAPL and NIPBL have opposite effects on cohesin’s association with DNA, we asked whether decreasing Wapl dosage could correct phenotypes seen in Nipbl +/− mice. Gene expression and embryonic growth are partially corrected, but perinatal lethality is not. Our data are consistent with the view that cohesin dynamics play a key role in regulating gene expression.

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The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism

Cited by 37 publications

References 45 publications

Contribution of variant subunits and associated factors to genome-wide distribution and dynamics of cohesin

Contribution of variant subunits and associated factors to genome-wide distribution and dynamics of cohesin

A model for Scc2p Stimulation of Cohesin’s ATPase and its Inhibition by Acetylation of Smc3p

Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl ^+/− embryos

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The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism

Cited by 37 publications

References 45 publications

Contribution of variant subunits and associated factors to genome-wide distribution and dynamics of cohesin

Contribution of variant subunits and associated factors to genome-wide distribution and dynamics of cohesin

A model for Scc2p Stimulation of Cohesin’s ATPase and its Inhibition by Acetylation of Smc3p

Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl +/− embryos

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Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl ^+/− embryos