Oncoprotein SS18-SSX is a hallmark of synovial sarcomas. However, as a part of the SS18-SSX fusion protein, SS18’s function remains unclear. Here, we depict the structures of both human SS18/BRG1 and yeast SNF11/SNF2 subcomplexes. Both subcomplexes assemble into heterodimers that share a similar conformation, suggesting that SNF11 might be a homologue of SS18 in chromatin remodeling complexes. Importantly, our study shows that the self-association of the intrinsically disordered region, QPGY domain, leads to liquid-liquid phase separation (LLPS) of SS18 or SS18-SSX and the subsequent recruitment of BRG1 into phase-separated condensates. Moreover, our results show that the tyrosine residues in the QPGY domain play a decisive role in the LLPS of SS18 or SS18-SSX. Perturbations of either SS18-SSX LLPS or SS18-SSX’s binding to BRG1 impair NIH3T3 cell transformation by SS18-SSX. Our data demonstrate that both LLPS and assembling into chromatin remodelers contribute to the oncogenic activity of SS18-SSX in synovial sarcomas.

During early mammalian embryogenesis, totipotent zygotes and early blastomeres undergo extensive post‐transcriptional regulation during the establishment of the first cell lineages; however, the functional contribution of alternative splicing to embryonic compaction and blastulation remains poorly understood. Here, we show that SF3B1, a core component of the spliceosome, is upregulated from the 4‐cell stage and mediates highly dynamic splicing programs. Depletion of SF3B1 results in developmental arrest at the morula stage, accompanied by widespread transcriptomic dysregulation characterized by aberrant expression of transcription factors that impede pluripotency transition. Alternative splicing analysis further identifies that aberrantly spliced transcripts were significantly enriched in genes involved in cell cycle regulation, such as Cdk11b and Ccnb1 . Importantly, we demonstrate that SF3B1 undergoes intrinsic, IDR‐driven liquid‐liquid phase separation both in vitro and in vivo, forming nuclear condensates in oocytes and early embryos, which is essential for successful development to the blastocyst stage. Together, our findings reveal that phase separation mediated SF3B1 splicing activity is a critical regulator of early mouse embryonic development.

Protein family membership may constrain protein thermal stability, but the extent of this effect remains unclear. We reanalyzed a published thermal proteome dataset containing 3917 Arabidopsis thaliana proteins. Proteins within the same family showed significantly smaller pairwise T_m differences than size-matched random groups, and family membership explained 67.6% of total T_m variation. Although thermal stability was generally conserved within families, some paralogs displayed marked divergence beyond that expected from sequence similarity. This exceptional divergence was not associated with duplication mode or overall structural distance, whereas differences in disulfide-bond density showed the clearest structural association. Gene Ontology cellular-component divergence was also positively associated with thermal divergence. Overall, thermal stability is strongly organized at the gene-family level, while exceptional divergence among paralogs appears to arise through heterogeneous, pair-specific structural and functional changes.

Liquid-liquid phase separation (LLPS) regulates protein function by organizing proteins into dynamic condensates, yet how divergence in LLPS among orthologs gives rise to species-specific functional outputs remains poorly understood. Here, we show that intrinsically disordered regions (IDRs) act as transferable modules whose sequence composition encodes phase separation capacity and functional outputs. Incorporating the QPGY domain from human SS18 into its yeast ortholog Snf11 yields a chimeric protein (Snf11-QPGY) that forms dynamic intracellular condensates. These condensates activate the adhesion genes FLO1 and FLO11, triggering calcium-dependent flocculation absent in wild-type cells. Mechanistically, Snf11-QPGY sequesters histone deacetylase subunit Rpd3 within condensates, reducing its occupancy at FLO promoters and promoting histone acetylation and transcriptional activation. Substituting QPGY with a heterologous LLPS-competent IDR restores condensate formation but does not recapitulate QPGY-driven transcriptional-phenotypic outputs. These findings reveal how evolutionary diversification of IDR sequences drives functional divergence among orthologs and offer a framework for engineering IDR-dependent regulatory modules.