Through the lens of phase separation: intrinsically unstructured protein and chromatin looping

Cai, Ling; Wang, Gang Greg

doi:10.1080/19491034.2023.2179766

Cited by 8 publications

(6 citation statements)

References 171 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although in this study we have been focused on the cohesin-dependent loop extrusion model, it is important to highlight that p53 has an intrinsically disordered domain 72 . Intrinsically disordered proteins have the capacity to undergo liquid-liquid phase separation to form membrane-less droplets that act as transcriptional condensates, promote gene expression, and remodel 3D chromatin organization 73 . However, to what extent p53 has the ability to induce topological changes in genome architecture through this mechanism and what the transcriptional consequences would be remains unknown.…”

Section: Discussionmentioning

confidence: 99%

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

Serra,

Nieto-Aliseda,

Fanlo-Escudero

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

Serra,

Nieto-Aliseda,

Fanlo-Escudero

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Although in this study we have been focused on the cohesin-dependent loop extrusion model, it is important to highlight that p53 has an intrinsically disordered domain 71 . Intrinsically disordered proteins have the capacity to undergo liquid-liquid phase separation to form membrane-less droplets that act as transcriptional condensates, promote gene expression, and remodel 3D chromatin organization 72 . However, to what extent p53 has the ability to induce topological changes in genome architecture through this mechanism and what the transcriptional consequences would be remains unknown.…”

Section: Discussionmentioning

confidence: 99%

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

Serra,

Nieto-Aliseda,

Fanlo

et al. 2023

Preprint

View full text Add to dashboard Cite

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, using a multi-omics integration framework, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains and DNA loops within minutes of its activation, which escort the p53 transcriptional program along time. Focused on p53-bound enhancers, we report a core transcriptional program of 340 genes directly regulated by p53 over distance, most of these not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Taken together, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help future designs of p53-based cancer therapies.

show abstract

“…Nonetheless, the ability of condensates to tune the rates of biochemical reactions is not only determined by their biochemical compositions. Dynamic properties, such as viscosities and molecular mobilities, also affect how condensates exchange biomolecules with the rest of the cell (9)(10)(11) and interact with other intracellular structures, such as chromatin (12) and cytoskeletal components (13). Dynamic properties are also directly relevant to condensate assembly and disassembly kinetics (14) and irreversible aging processes (15).…”

Section: Introductionmentioning

confidence: 99%

Active learning of the thermodynamics-dynamics trade-off in protein condensates

An,

Webb,

Jacobs

2024

Sci. Adv.

View full text Add to dashboard Cite

Phase-separated biomolecular condensates exhibit a wide range of dynamic properties, which depend on the sequences of the constituent proteins and RNAs. However, it is unclear to what extent condensate dynamics can be tuned without also changing the thermodynamic properties that govern phase separation. Using coarse-grained simulations of intrinsically disordered proteins, we show that the dynamics and thermodynamics of homopolymer condensates are strongly correlated, with increased condensate stability being coincident with low mobilities and high viscosities. We then apply an “active learning” strategy to identify heteropolymer sequences that break this correlation. This data-driven approach and accompanying analysis reveal how heterogeneous amino acid compositions and nonuniform sequence patterning map to a range of independently tunable dynamic and thermodynamic properties of biomolecular condensates. Our results highlight key molecular determinants governing the physical properties of biomolecular condensates and establish design rules for the development of stimuli-responsive biomaterials.

show abstract

Through the lens of phase separation: intrinsically unstructured protein and chromatin looping

Cited by 8 publications

References 171 publications

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

Active learning of the thermodynamics-dynamics trade-off in protein condensates

Contact Info

Product

Resources

About