scholarly journals Characterization of Liquid-liquid phase Separation in 3D Genome Organization

2020 ◽  
Author(s):  
Tingting Li ◽  
Jiaqing Xing ◽  
Tao Li ◽  
Teng Li ◽  
Weihua Li
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Genome Organization ◽  
Enrichment Analysis ◽  
Liquid Phase Separation ◽  
Rna Recognition Motif ◽  
3D Genome ◽  
Shiny App ◽  
Modular Domains ◽  
Liquid Liquid Phase Separation

Abstract Many proteins have been demonstrated to participate in 3D genome organization through liquid-liquid phase separation (LLPS) such as RNPII, HP1a. However, systematic investigation of relationships between LLPS and 3D genome organization remains lacking. Here, we predicted the intrinsic disordered regions (IDRs) and modular domains of all human proteins and performed GSEA analysis according to their proportions of IDRs. Our results showed that main biological processes involved in 3D genome organization are highly enriched with IDRs, including chromatin organization, RNA splicing and histone modification, demonstrating the key role of LLPS in regulating nuclear structure. Of the 3885 IDR-rich proteins, 1427 proteins are involved in 3D genome organization. IDR regions of these proteins have strong preference of Ser, Leu, Pro, Ala, Gly, Glu and Lys, and lack of hydrophobic amino acids such as Trp, Tyr, Phe and Met, suggesting dipolar interactions rather than aromatic-involved interactions involved. Further motif enrichment analysis suggests that RNA recognition motif and zinc finger motif are the two most abundant repeatedly-occurred modular domains within IDR-containing proteins. Finally, we developed a Shiny APP named phasepro that interactively analyze and visualize a protein’s potential of LLPS, including IDRs, motifs, amino acid preferences and electric charges.

scholarly journals Suppression of liquid-liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells

2020 ◽  
Author(s):  
Sergey V. Ulianov ◽  
Artem K. Velichko ◽  
Mikhail D. Magnitov ◽  
Artem V. Luzhin ◽  
Arkadiy K. Golov ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Spatial Organization ◽  
Living Cells ◽  
Liquid Phase Separation ◽  
Nuclear Space ◽  
3D Genome ◽  
Chromatin Folding ◽  
Optical Reconstruction ◽  
Liquid Liquid Phase Separation

AbstractLiquid-liquid phase separation (LLPS) contributes to the spatial and functional segregation of molecular processes. However, the role played by LLPS in chromatin folding in living cells remains unclear. Here, using stochastic optical reconstruction microscopy (STORM) and Hi-C techniques, we studied the effects of 1,6-hexanediol (1,6-HD)-mediated LLPS modulation on higher-order chromatin organization in living cells. We found that 1,6-HD treatment caused the enlargement of nucleosome nanodomains and their more uniform distribution in the nuclear space. At a megabase-scale, chromatin underwent moderate but irreversible perturbations that resulted in the partial mixing of A and B compartments. The removal of 1,6-HD from the culture medium did not allow chromatin to acquire initial configurations, but increased further mixing of the chromatin compartments and resulted in more compact repressed chromatin than in untreated cells. 1,6-HD treatment also weakened enhancer-promoter interactions but did not considerably affect CTCF-dependent loops. Our results suggest that 1,6-HD-sensitive LLPS plays a limited role in chromatin spatial organization by constraining its folding patterns and facilitating compartmentalization at different levels.

scholarly journals Suppression of liquid–liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells

2021 ◽  
Author(s):  
Sergey V Ulianov ◽  
Artem K Velichko ◽  
Mikhail D Magnitov ◽  
Artem V Luzhin ◽  
Arkadiy K Golov ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Spatial Organization ◽  
Living Cells ◽  
Liquid Phase Separation ◽  
Nuclear Space ◽  
3D Genome ◽  
Chromatin Folding ◽  
Optical Reconstruction ◽  
Liquid Liquid Phase Separation

Abstract Liquid–liquid phase separation (LLPS) contributes to the spatial and functional segregation of molecular processes within the cell nucleus. However, the role played by LLPS in chromatin folding in living cells remains unclear. Here, using stochastic optical reconstruction microscopy (STORM) and Hi-C techniques, we studied the effects of 1,6-hexanediol (1,6-HD)-mediated LLPS disruption/modulation on higher-order chromatin organization in living cells. We found that 1,6-HD treatment caused the enlargement of nucleosome clutches and their more uniform distribution in the nuclear space. At a megabase-scale, chromatin underwent moderate but irreversible perturbations that resulted in the partial mixing of A and B compartments. The removal of 1,6-HD from the culture medium did not allow chromatin to acquire initial configurations, and resulted in more compact repressed chromatin than in untreated cells. 1,6-HD treatment also weakened enhancer-promoter interactions and TAD insulation but did not considerably affect CTCF-dependent loops. Our results suggest that 1,6-HD-sensitive LLPS plays a limited role in chromatin spatial organization by constraining its folding patterns and facilitating compartmentalization at different levels.

scholarly journals Biomolecular condensates as arbiters of biochemical reactions inside the nucleus

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Guillaume Laflamme ◽  
Karim Mekhail
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Environmental Conditions ◽  
Genome Organization ◽  
Liquid Phase Separation ◽  
Nuclear Space ◽  
Biological Processes ◽  
Biochemical Reactions ◽  
Dynamic Structures ◽  
Liquid Liquid Phase Separation

AbstractLiquid-liquid phase separation (LLPS) has emerged as a central player in the assembly of membraneless compartments termed biomolecular condensates. These compartments are dynamic structures that can condense or dissolve under specific conditions to regulate molecular functions. Such properties allow biomolecular condensates to rapidly respond to changing endogenous or environmental conditions. Here, we review emerging roles for LLPS within the nuclear space, with a specific emphasis on genome organization, expression and repair. Our review highlights the emerging notion that biomolecular condensates regulate the sequential engagement of molecules in multistep biological processes.

scholarly journals Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydrophobic Interaction ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation

scholarly journals Amyloid Aggregation under the Lens of Liquid–Liquid Phase Separation

2020 ◽  
pp. 368-378
Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Amyloid Aggregation ◽  
Liquid Liquid Phase Separation

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

Sign in / Sign up

Export Citation Format

Share Document