Mammalian SWI/SNF chromatin remodeling complexes modulate DNA accessibility and gene expression; however, their genomic targeting mechanisms remain incompletely understood. Here, we identify SWIFT (SW...

Niekamp et al. show that biomolecular condensates formed by Polycomb repressive complexes can physically restrict access of the activating remodeler SWI/SNF to chromatin. Establishing this barrier dep...

Synovial sarcoma is driven by the SS18-SSX fusion oncoprotein, which has been assumed to promote tumorigenesis through its incorporation into the SWI/SNF chromatin remodeling complexes. Accordingly, therapeutic efforts have focused on targeting SS18-SSX containing SWI/SNF assemblies, yet these approaches have produced limited clinical benefit. Here, we demonstrate that SS18-SSX sustains oncogenic transcription independent of SWI/SNF activity. Despite efficient degradation and dismantling of SWI/SNF complexes, fusion occupancy at target loci and associated gene expression programs remain largely intact. Instead, we identify the acetyltransferase P300 as an essential co-factor supporting SS18-SSX chromatin binding and transcriptional activation. Targeting P300 displaces the fusion from chromatin, suppresses its transcriptional output, compromising synovial sarcoma viability. Notably, dual PROTAC mediated degradation of P300 and SWI/SNF produces strong synergistic effects, broadly disrupting SS18-SSX localization and function. These findings redefine the mechanistic basis of synovial sarcoma and reveal a mechanistically anchored therapeutic strategy for targeting its core oncogenic driver. ### Competing Interest Statement C.R.V. has been a consultant for Flare Therapeutics, Roivant Sciences and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals and Treeline Biosciences; has received research funding from Boehringer Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. S.A.A. has been a consultant and/or shareholder for Neomorph, Imago Biosciences, Hyku Therapeutics, C4 Therapeutics, Accent Therapeutics and Nimbus Therapeutics; and has received research support from Janssen and Syndax. N.O.C. is a co-founder, shareholder and management consultant for PhenoTherapeutics Ltd; and a shareholder in Amplia Therapeutics Ltd All other authors declare no financial interests UKRI, EP/X039633/1 Worldwide Cancer Research, https://ror.org/031tfbz57, 21-0271 Science Foundation Ireland, https://ror.org/0271asj38, 18/SIRG/5573

By mapping SWI/SNF complex subfamilies in the melanocytic lineage, Grossi and Nguyen et al. find that PBAF-only sites harbor PRC1/2 modifications and the repressive transcription factor REST. PBAF is ...

Cryo-EM and genetic analyses reveal that the SWI/SNF chromatin remodeler is an integral component of the transcription pre-initiation complex. The structures demonstrate how SWI/SNF facilitates transcription initiation through stabilization of PIC organization and concerted remodeling of the +1 nucleosome.

Abstract. The SWI/SNF family of chromatin remodelling complexes, comprising BAF, PBAF and ncBAF, is known for their critical roles in regulating chromatin

The mechanisms directing chromatin remodeling complexes to genomic regions have remained elusive. Here, the authors show that lncRNAs direct SWI/SNF to cell type-specific enhancers, investigating an R...

Mutations in genes that encode subunits of the SWI/SNF chromatin remodelling complexes are found in more than 20% of cancers as well as in certain neurodevelopmental disorders. This Review discusses mechanisms...

Niekamp et al. show that biomolecular condensates formed by Polycomb repressive complexes can physically restrict access of the activating remodeler SWI/SNF to chromatin. Establishing this barrier depends on Polycomb complex composition and which complex binds to chromatin first, revealing the ways that material properties of chromatin regulators help balance gene expression levels.

Niekamp et al. show that biomolecular condensates formed by Polycomb repressive complexes can physically restrict access of the activating remodeler SWI/SNF to chromatin. Establishing this barrier depends on Polycomb complex composition and which complex binds to chromatin first, revealing the ways that material properties of chromatin regulators help balance gene expression levels.

The SWI/SNF complex is an essential chromatin remodeler that regulates DNA accessibility during brain development. Through combinatorial assembly of subunits encoded by paralogous genes, SWI/SNF compl...