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Stochastic particle unbinding modulates growth dynamics and size of transcription factor condensates in living cells

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dc.contributor.author Muñoz-Gil, Gorka
dc.contributor.author Romero-Aristizabal, Catalina
dc.contributor.author Mateos, Nicolas
dc.contributor.author Campelo, Felix
dc.contributor.author De Llobet, Lara Isabel
dc.contributor.author Beato, Miguel
dc.contributor.author Lewenstein, Maciej
dc.contributor.author Garcia-Parajo, Maria F.
dc.contributor.author Torreno-Pina, Juan A.
dc.date.accessioned 2022-11-08T07:13:00Z
dc.date.available 2022-11-08T07:13:00Z
dc.date.issued 2022
dc.identifier.citation Muñoz-Gil G, Romero-Aristizabal C, Mateos N, Campelo F, de Llobet Cucalon LI, Beato M, Lewenstein M, Garcia-Parajo MF, Torreno-Pina JA. Stochastic particle unbinding modulates growth dynamics and size of transcription factor condensates in living cells. Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2200667119. DOI: 10.1073/pnas.2200667119
dc.identifier.issn 0027-8424
dc.identifier.uri http://hdl.handle.net/10230/54745
dc.description.abstract Liquid-liquid phase separation (LLPS) is emerging as a key physical principle for biological organization inside living cells, forming condensates that play important regulatory roles. Inside living nuclei, transcription factor (TF) condensates regulate transcriptional initiation and amplify the transcriptional output of expressed genes. However, the biophysical parameters controlling TF condensation are still poorly understood. Here we applied a battery of single-molecule imaging, theory, and simulations to investigate the physical properties of TF condensates of the progesterone receptor (PR) in living cells. Analysis of individual PR trajectories at different ligand concentrations showed marked signatures of a ligand-tunable LLPS process. Using a machine learning architecture, we found that receptor diffusion within condensates follows fractional Brownian motion resulting from viscoelastic interactions with chromatin. Interestingly, condensate growth dynamics at shorter times is dominated by Brownian motion coalescence (BMC), followed by a growth plateau at longer timescales that result in nanoscale condensate sizes. To rationalize these observations, we extended on the BMC model by including the stochastic unbinding of particles within condensates. Our model reproduced the BMC behavior together with finite condensate sizes at the steady state, fully recapitulating our experimental data. Overall, our results are consistent with condensate growth dynamics being regulated by the escaping probability of PR molecules from condensates. The interplay between condensation assembly and molecular escaping maintains an optimum physical condensate size. Such phenomena must have implications for the biophysical regulation of other nuclear condensates and could also operate in multiple biological scenarios.
dc.description.sponsorship The research leading to these results has received funding from BIST-Ignite funding (PHASE-CHROM) (to C.R.-A. and J.A.T.-P.); the European Commission H2020 Program under grant agreement ERC Adv788546 (NANO-MEMEC) (to M.F.G.-P.), ERC AdG NOQIA and EU Horizon 2020 FET-OPEN OPTOlogic (Grant No 899794) (to M.L.), and ERC Synergy Grant 609989 (to M.B.); the Government of Spain (Severo Ochoa CEX2019-000910-S (to M.L. and to M.F.G.P.), JdC-IJCI-2017-33160 (to J.A.T.-P.), (PGC2018-097027-B-I00/10.13039/501100011033, CEX2019-000910-S/10.13039/501100011033 and QUSPIN RTC2019-007196-7) (to M.L.), the State Research Agency (FIDEUA PID2019-106901GB-I00/10.13039/501100011033) (to M.L.), PID2020-113068RB-I00/10.13039/501100011033 (to M.F.G.-P.) and (RYC-2017–22227 and PID2019-106232RB-I00/10.13039/501100011033) (to F.C.); QuantumCAT_U16-011424 (to M.L.), co-funded by the ERDF Operational Program of Catalonia 2014-2020; (QUANTERA MAQS (funded by the State Research Agency under PCI2019-111828-2/321 10.13039/501100011033) and QUANTERA DYNAMITE PCI2022-132919) (to M.L.); Barcelona Supercomputing Center MareNostrum (FI-2022-1-0042) (to M.L.); Obra Social La Caixa (LCF-ICFO) and the Austrian Science Fund (FWF) through SFB BeyondC F7102 (to G.M.-G.); National Science Centre, Poland (Symfonia Grant No. 2016/20/W/ST4/00314) (to M.L.); Fundació CELLEX (Barcelona); Fundació Mir-Puig; and the Generalitat de Catalunya through the CERCA program and AGAUR (grant no. 2017 SGR 1341 to M.L. and no. 2017SGR1000 to M.F.G.-P.).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher National Academy of Sciences
dc.relation.ispartof Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2200667119
dc.rights © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.title Stochastic particle unbinding modulates growth dynamics and size of transcription factor condensates in living cells
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1073/pnas.2200667119
dc.subject.keyword Brownian motion coalescence
dc.subject.keyword Biomolecular condensates
dc.subject.keyword Liquid–liquid phase separation
dc.subject.keyword Single particle tracking
dc.subject.keyword Transcription factor
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/788546
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/899794
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609989
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-097027-B-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTC2019-007196-7
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106901GB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-113068RB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106232RB-I00
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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