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1. Splicing regulation through biomolecular condensates and membraneless organelles

   https://doi.org/10.1038/s41580-024-00739-7  

   Giudice, Jimena; Jiang, Hao (September 2024, Nature Reviews Molecular Cell Biology)

   Zlotorynski, Eytan (Ed.)

   Biomolecular condensates, sometimes also known as membraneless organelles (MLOs), can form through weak multivalent intermolecular interactions of proteins and nucleic acids, a process often associated with liquid-liquid phase separation. Biomolecular condensates are emerging as sites and regulatory platforms of vital cellular functions, including transcription and RNA processing. In the first part of this Review, we comprehensively discuss how alternative splicing regulates the formation and properties of condensates, and conversely the roles of biomolecular condensates in splicing regulation. In the second part, we focus on the spatial connection between splicing regulation and nuclear MLOs such as transcriptional condensates, splicing condensates and nuclear speckles. We then discuss key studies showing how splicing regulation through biomolecular condensates is implicated in human pathologies such as neurodegenerative diseases, different types of cancer, developmental disorders and cardiomyopathies, and conclude with a discussion of outstanding questions pertaining to the roles of condensates and MLOs in splicing regulation and how to experimentally study them. 

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2. STI1 domain engages transient helices to mediate Dsk2 phase separation and proteasome condensation

   https://doi.org/10.1038/s44318-026-00696-1  

   Acharya, Nirbhik; Daniel, Emily A; Dao, Thuy P; Niblo, Jessica K; Mulvey, Erin O; Sukenik, Shahar; Kraut, Daniel A; Roelofs, Jeroen; Castañeda, Carlos A (April 2026, The EMBO Journal)

   Abstract Ubiquitin-binding shuttle proteins are important components of stress-induced biomolecular condensates in cells. Yeast Dsk2 scaffolds proteasome-containing condensates via multivalent interactions with proteasomes and polyubiquitinated substrates under stress conditions. Here, we identify the chaperone-binding STI1 domain as the main driver of Dsk2 self-association and phase separation. Using nuclear magnetic resonance (NMR) spectroscopy and computational simulations, we find that the STI1 domain interacts with three transient amphipathic helices within the intrinsically disordered regions of Dsk2. Removal of either the STI1 domain or these helices significantly reduces Dsk2’s propensity to form condensates. In vivo, perturbing STI1-helix interactions, specifically removal of the transient helices, reduces the formation of azide stress-induced Dsk2/proteasome condensates, in line with our in vitro results. Modeling of Dsk2 STI1-helix interactions reveals a binding mode reminiscent of chaperone STI1/DP2 domains interacting with client helices. Our findings support a model whereby STI1-helix interactions important for Dsk2 condensate formation can be replaced by STI1-client interactions for downstream chaperone or other protein quality control outcomes. 

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3. The condensation of HP1α/Swi6 imparts nuclear stiffness

   https://doi.org/10.1016/j.celrep.2024.114373  

   Williams, Jessica F; Surovtsev, Ivan V; Schreiner, Sarah M; Chen, Ziyuan; Raiymbek, Gulzhan; Nguyen, Hang; Hu, Yan; Biteen, Julie S; Mochrie, Simon GJ; Ragunathan, Kaushik; et al (July 2024, Cell Reports)

   Biomolecular condensates have emerged as major drivers of cellular organization. It remains largely unexplored, however, whether these condensates can impart mechanical function(s) to the cell. The heterochromatin protein HP1α (Swi6 in Schizosaccharomyces pombe) crosslinks histone H3K9 methylated nucleosomes and has been proposed to undergo condensation to drive the liquid-like clustering of heterochromatin domains. Here, we leverage the genetically tractable S. pombe model and a separation-of-function allele to elucidate a mechanical function imparted by Swi6 condensation. Using single-molecule imaging, force spectroscopy, and high-resolution live-cell imaging, we show that Swi6 is critical for nuclear resistance to external force. Strikingly, it is the condensed yet dynamic pool of Swi6, rather than the chromatin-bound molecules, that is essential to imparting mechanical stiffness. Our findings suggest that Swi6 condensates embedded in the chromatin meshwork establish the emergent mechanical behavior of the nucleus as a whole, revealing that biomolecular condensation can influence organelle and cell mechanics. 

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4. Chromatin heterogeneity modulates nuclear condensate dynamics and phase behavior

   https://doi.org/10.1038/s41467-025-60771-9  

   Xia, Jing; Zhao, Jessica Z; Strom, Amy R; Brangwynne, Clifford P (December 2025, Nature Communications)

   Abstract The cell nucleus is a soft composite material with a shell-like nuclear cortex enclosing chromatin, comprised of roughly 2 meters of DNA and associated proteins. Assembling on and around chromatin are droplet-like structures known as biomolecular condensates, which form via phase separation, and facilitate vital roles in gene expression. From studies in non-living materials, the driving forces for phase separation are expected to be sensitive to the local mechanical environment, which often exhibits significant spatial heterogeneity. However, the relationship between chromatin heterogeneity and the phase equilibrium and dynamics of nuclear condensates remains unclear. Here, we investigate the interplay between chromatin organization and the formation, dynamics, and size of engineered model condensates and endogenous nuclear bodies in living cells. We demonstrate that decreasing chromatin heterogeneity with epigenetic modifying drugs correlates with decreased mobility of both endogenous and engineered condensates, and is associated with impaired condensate growth and shifts in the binodal phase boundary of engineered condensates. These findings illustrate how the cell nucleus behaves as a heterogeneous composite material with mechanically permissive chromatin micro-environments. 

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5. A model for organization and regulation of nuclear condensates by gene activity

   https://doi.org/10.1038/s41467-023-39878-4  

   Schede, Halima H.; Natarajan, Pradeep; Chakraborty, Arup K.; Shrinivas, Krishna (December 2023, Nature Communications)

   Abstract Condensation by phase separation has recently emerged as a mechanism underlying many nuclear compartments essential for cellular functions. Nuclear condensates enrich nucleic acids and proteins, localize to specific genomic regions, and often promote gene expression. How diverse properties of nuclear condensates are shaped by gene organization and activity is poorly understood. Here, we develop a physics-based model to interrogate how spatially-varying transcription activity impacts condensate properties and dynamics. Our model predicts that spatial clustering of active genes can enable precise localization and de novo nucleation of condensates. Strong clustering and high activity results in aspherical condensate morphologies. Condensates can flow towards distant gene clusters and competition between multiple clusters lead to stretched morphologies and activity-dependent repositioning. Overall, our model predicts and recapitulates morphological and dynamical features of diverse nuclear condensates and offers a unified mechanistic framework to study the interplay between non-equilibrium processes, spatially-varying transcription, and multicomponent condensates in cell biology. 

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