Chromatin-organizing cohesin complex cooperates with transcription factor IRF8 to enable the functionality of dendritic cells in vivo.

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

We are looking for a Full Professor in the Biophysics chair group, part of Wageningen University & Research (WUR)

Chromosome conformation capture (3C)-derived methods have become an indispensable tool in the study of gene regulation. The three-dimensional contacts they are able to assay depend strongly on the properties of the enzyme used to fragment chromatin prior to proximity-driven ligation. Micrococcal nuclease (MNase), used in Micro-C, increases resolution at the expense of low ligation efficiency and the need for extensive enzyme titration. To overcome these limitations, we engineered a highly active, TEV protease-activatable caspase-activated DNase (CAD) to enable an efficient, low-sequence-bias, and high-resolution proximity ligation assay we call CAD-C. CAD-C was successful on the first attempt for each human cell line tested and the resulting datasets capture loops, TADs, compartments, and stripes similarly to Micro-C. However, compared to Micro-C and Hi-C, CAD-C shows enhanced sensitivity for promoter-enhancer loops. Leveraging the ligation-competent DNA ends produced by CAD cleavage, we show that CAD-C is compatible with a highly streamlined, repair-free protocol and produces multi-step CADwalks, consecutive ligations between nucleosomal or sub-nucleosomal fragments. With these walks, we probe local chromatin fiber folding contacts, nucleosomal and sub-nucleosomal footprints, and long-range nuclear organization regimes in human cell lines. CAD-C is an efficient, robust chromatin structure assay that can span sub-nucleosomal to chromosomal length scales in a single experiment. ### Competing Interest Statement V.I.R. and J.S. are inventors on a related patent application covering CAD-C (PCT application filed 2024). NIH Common Fund, https://ror.org/001d55x84, 1DP2GM150021 Irma T. Hirschl Trust, https://ror.org/01yaqvf46, Career Scientist Award Rita Allen Foundation, https://ror.org/0515k5w36, Scholar Award Stavros Niarchos Foundation, https://ror.org/0210rze73, Institute for Global Infectious Disease Research at Rockefeller University Grant Robertson Technology Development Fund at Rockefeller University Boehringer Ingelheim (Germany), https://ror.org/00q32j219, PhD Fellowship to JS U.S. National Science Foundation, https://ror.org/021nxhr62, GRFP to LAW International Human Frontier Science Program Organization, https://ror.org/02ebx7v45, Postdoctoral Cross-Disciplinary Fellowship to AO Natural Sciences and Engineering Research Council of Canada, Postgraduate fellowship to HC, Postgraduate fellowship to JLY

Scientific data can be beautiful. An example where the data itself have a particularly striking appearance even before any scientific meaning has been ascribed

Call for Academic and Industrial Postdoctoral Fellowships in Data-Driven Life Science 2026 Generic Description of the DDLS Postdoc Program The SciLifeLab and Wallenberg National Program for Data-Drive...

Academic publishing now shows the same decline that has hit social media and online marketplaces.

Schooley et al. find that mitotically bookmarked loci drive a transient chromosome folding state during G1 entry that is subsequently modulated by factors inherited through the cytoplasm.

During eukaryotic transcription, Pol II must overcome nucleosome obstacles and, because of DNA’s helical structure, must also rotate relative to DNA, generating torsional stress. However, there is lim...

Backed by the Government of Canada’s $1.7 billion Global Impact+ Research Talent Initiative, Dalhousie University is undertaking one of the most ambitious research-leader recruitment efforts in its hi...

Our genomes are highly structured, which facilitates gene regulation. An ambitious project has catalogued the organization of DNA in the nuclei of human cells.

The 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitatin...