Phase Transitions of Associative Biomacromolecules

Chemical Reviews, Год журнала: 2023, Номер 123(14), С. 8945 - 8987

Опубликована: Март 7, 2023

Multivalent proteins and nucleic acids, collectively referred to as multivalent associative biomacromolecules, provide the driving forces for formation compositional regulation of biomolecular condensates. Here, we review key concepts phase transitions aqueous solutions specifically that include folded domains intrinsically disordered regions. The these systems come under rubric coupled segregative transitions. underlying processes are presented, their relevance condensates is discussed.

Язык: Английский

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Short tandem repeats bind transcription factors to tune eukaryotic gene expression

Science, Год журнала: 2023, Номер 381(6664)

Опубликована: Сен. 21, 2023

Short tandem repeats (STRs) are enriched in eukaryotic cis-regulatory elements and alter gene expression, yet how they regulate transcription remains unknown. We found that STRs modulate factor (TF)-DNA affinities apparent on-rates by about 70-fold directly binding TF DNA-binding domains, with energetic impacts exceeding many consensus motif mutations. maximize the number of weakly preferred microstates near target sites, thereby increasing density, well predicted statistical mechanics. Confirming also affect cells, neural networks trained only on vivo occupancies effects identical to those observed vitro. Approximately 90% TFs preferentially bound need not resemble known motifs, providing a mechanism genomic sites.

Язык: Английский

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RNA granules: functional compartments or incidental condensates?

Genes & Development, Год журнала: 2023, Номер 37(9-10), С. 354 - 376

Опубликована: Май 1, 2023

RNA granules are mesoscale assemblies that form in the absence of limiting membranes. contain factors for biogenesis and turnover often assumed to represent specialized compartments biochemistry. Recent evidence suggests assemble by phase separation subsoluble ribonucleoprotein (RNP) complexes partially demix from cytoplasm or nucleoplasm. We explore possibility some nonessential condensation by-products arise when RNP exceed their solubility limit as a consequence cellular activity, stress, aging. describe use evolutionary mutational analyses single-molecule techniques distinguish functional "incidental condensates."

Язык: Английский

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Phase Separation in Biology and Disease; Current Perspectives and Open Questions

Journal of Molecular Biology, Год журнала: 2023, Номер 435(5), С. 167971 - 167971

Опубликована: Янв. 21, 2023

In the past almost 15 years, we witnessed birth of a new scientific field focused on existence, formation, biological functions, and disease associations membraneless bodies in cells, now referred to as biomolecular condensates. Pioneering studies from several laboratories [reviewed in1, 2, 3] supported model wherein condensates associated with diverse processes form through process phase separation. These other findings that followed have revolutionized our understanding how biomolecules are organized space time within cells perform myriad including cell fate determination, signal transduction, endocytosis, regulation gene expression protein translation, RNA metabolism. Further, formed aberrant transitions been numerous human diseases, prominently neurodegeneration cancer. While some cases, rigorous evidence supports links between formation separation many others such less robustly supported, which has led rightful scrutiny generality roles biology disease.4, 5, 6, 7 During week-long workshop March 2022 at Telluride Science Research Center (TSRC) Telluride, Colorado, ∼25 scientists addressed key questions surrounding field. Herein, present insights gained these discussions, addressing topics including, systems, normal states, their applications synthetic biology, potential for therapeutically targeting

Язык: Английский

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Transcriptional condensates: a blessing or a curse for gene regulation?

Communications Biology, Год журнала: 2024, Номер 7(1)

Опубликована: Фев. 16, 2024

Whether phase-separation is involved in the organization of transcriptional machinery and if it aids or inhibits process a matter intense debate. In this Mini Review, we will cover current knowledge regarding role condensates on gene expression regulation. We summarize latest discoveries relationship between condensate formation, genome organization, activity, focusing strengths weaknesses experimental approaches used to interrogate these aspects transcription living cells. Finally, discuss challenges for future research.

Язык: Английский

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Transcription factor clusters enable target search but do not contribute to target gene activation

Nucleic Acids Research, Год журнала: 2023, Номер 51(11), С. 5449 - 5468

Опубликована: Март 29, 2023

Many transcription factors (TFs) localize in nuclear clusters of locally increased concentrations, but how TF clustering is regulated and it influences gene expression not well understood. Here, we use quantitative microscopy living cells to study the regulation function budding yeast Gal4 its endogenous context. Our results show that forms overlap with GAL loci. Cluster number, density size are different growth conditions by Gal4-inhibitor Gal80 concentration. truncation mutants reveal facilitated by, does completely depend on DNA binding intrinsically disordered regions. Moreover, discover acts as a double-edged sword: self-interactions aid recruitment target genes, recruited molecules DNA-bound do contribute to, may even inhibit, activation. We propose need balance effects search activation facilitate proper expression.

Язык: Английский

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Single-molecule tracking (SMT): a window into live-cell transcription biochemistry

Biochemical Society Transactions, Год журнала: 2023, Номер 51(2), С. 557 - 569

Опубликована: Март 6, 2023

How molecules interact governs how they move. Single-molecule tracking (SMT) thus provides a unique window into the dynamic interactions of biomolecules within live cells. Using transcription regulation as case study, we describe SMT works, what it can tell us about molecular biology, and has changed our perspective on inner workings nucleus. We also cannot yet new technical advances seek to overcome its limitations. This ongoing progress will be imperative address outstanding questions machines function in

Язык: Английский

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Epigenetic mechanisms to propagate histone acetylation by p300/CBP

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 17, 2023

Histone acetylation is important for the activation of gene transcription but little known about its direct read/write mechanisms. Here, we report cryogenic electron microscopy structures in which a p300/CREB-binding protein (CBP) multidomain monomer recognizes histone H4 N-terminal tail (NT) (ac) nucleosome and acetylates non-H4 NTs within same nucleosome. p300/CBP not only recognized H4NTac via bromodomain pocket responsible reading, also interacted with DNA minor grooves outside that pocket. This directed catalytic center to one NTs. The primary target p300 writes by reading was H2BNT, H2BNTac promoted H2A-H2B dissociation from We propose model replicates H3-H4 tetramer inherit epigenetic storage, transcribes it H2B-H2A dimers activate context-dependent through local destabilization.

Язык: Английский

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p300 is an obligate integrator of combinatorial transcription factor inputs

Molecular Cell, Год журнала: 2023, Номер 84(2), С. 234 - 243.e4

Опубликована: Дек. 29, 2023

Transcription coactivators are proteins or protein complexes that mediate transcription factor (TF) function. However, they lack DNA-binding capacity, prompting the question of how engage target loci. Three non-exclusive hypotheses have been posited: recruited by complexing with TFs, binding histones through epigenetic reader domains, partitioning into condensates their extensive intrinsically disordered regions. Using p300 as a prototypical coactivator, we systematically mutated its annotated domains and show single-molecule tracking in live U2OS cells coactivator-chromatin depends entirely on combinatorial multiple TF-interaction domains. Furthermore, demonstrate acetyltransferase activity opposes p300-chromatin association N-terminal regulate activity. Single insufficient for chromatin regulation catalytic activity, implying principle speculate could broadly apply to eukaryotic gene regulation: TF must act coordination other TFs recruit coactivator

Язык: Английский

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Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair

Molecular Cell, Год журнала: 2023, Номер 83(10), С. 1640 - 1658.e9

Опубликована: Апрель 13, 2023

Язык: Английский

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