Study: Major Nuclear Protein Complexes Control Specialized Gene Regulation in Cancer and Beyond

Precision and timing of gene expression are essential for normal biological functions and, when disrupted, can lead to many human diseases, including cancers. However, how molecular machines—protein complexes—that control gene expression locate to specific genes at specific times within the nuclei of our cells has remained a mystery.

Now, scientists at Dana-Farber Cancer Institute have discovered a new protein domain, SWIFT, found in a major family of chromatin remodeling complexes called mammalian SWI/SNF (mSWI/SNF or BAF) complexes, which helps these regulatory machines target specific genes to activate their expression. Their study was funded by the National Institutes of Health, Pew-Stewart Scholars Program in Cancer Research, American Cancer Society Research Scholar Program, and others.

The findings, published in Science, reveal how the SWIFT platform on mSWI/SNF complexes engages transcription factors (TF) to enable specialized cellular functions during both normal development and cancer. Particularly in human cancers, SWIFT-TF engagement sustains cancer-promoting gene expression and cell growth. Notably, disrupting interactions with mutations halts cancer cell growth, flagging this new SWIFT-TF platform as a promising target for small-molecule development.[1]

Inside each of our trillions of cells, there are two meters of DNA that have 20,000 different genes that must be turned on and off at the right times for proper cellular function—a process known as gene regulation, which Cigall Kadoch, Ph.D.,, a professor of pediatric oncology at Dana-Farber and senior author of the study, likens to playing distinct chords on a piano with different sets of notes resulting in different output sounds.

One of the key regulators of gene expression studied by Dana-Farber’s Kadoch Lab is the mSWI/SNF chromatin remodeling complex. This large, multi-component protein machine helps coordinate the way our genome is made accessible so that genes can be activated at the right times and, reciprocally, so other genes are held “off” to avoid abnormal triggering of gene expression.

“We have had a long-standing interest in understanding the structural and biochemical features that govern mSWI/SNF complex remodeling, especially motivated by the fact that these complexes are mutated in over 20% of cancers,” Kadoch explained.

“Their outsized involvement in cancer has been one of the biggest findings from the sequencing era, bringing a lot of attention to this area of biology,” she added.

SWIFT domains
Components of mSWI/SNF complexes include proteins called SMARCD subunits, a family of three proteins, SMARCD1, D2, and D3, that each assemble in a mutually exclusive manner and have cell type-specific expression patterns across the cells of our body. Within each of these proteins, the SWIFT domains enable binding to distinct collections of TFs, a new finding from this work that explains the basis of SMARCD tissue specificity and supports opportunities to therapeutically disrupt specific groups of TFs and their activities.

“Oftentimes when a transcription factor is overexpressed in a given cancer type, the cancer cells become highly dependent on mSWI/SNF complexes and their remodeling activities,” Kadoch said.

“The mechanism behind why these cancers are so dependent has, until this work, remained quite elusive.”

Highly expresses
In blood cancers, such as acute myeloid leukemia (AML), the PU.1 (also called SPI1) transcription factor is highly expressed and represents a top dependency or vulnerability.  Kadoch and her team found that a single mutation in the SWIFT domain can break PU.1’s pro-cancer function, highlighting the criticality of the SWIFT-TF interface.

“Further, we found that dominant expression of the SWIFT domain in isolation prevents cancer-promoting transcription factors from binding mSWI/SNF complexes and dragging them to their target genes, halting cancer cell proliferation,” noted Siddhant Jain, Ph.D., the study’s first author and a Dana-Faber postdoctoral fellow at the department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, in Boston, MA.

“This underscores what a broad, major platform SWIFT is for human TFs; the more we know about the nature of these interactions, the more readily we expect to be able to design and develop targeted therapeutics with utility in different disease settings,” Jain added.

Notably, mSWI/SNF complexes perform important functions in our normal cells and tissues, and as such, drugging complexes systemically can present toxicity-related challenges. By understanding the SWIFT domain and even SMARCD subunit-specific SWIFT domains, this research now opens up the possibility of developing specialized small molecules that block specific TF interactions that uphold human cancer and other disease states.

Cancer’s dependency
“This work is very exciting for the research community because it mechanistically explains the dependency of many cancers on this broadly commissioned chromatin remodeling complex, and also now gives us an important toehold to be able to design strategies toward highly targeted therapeutic inhibition,” Kadoch concluded.

Reference
[1] Jain SU, Williamson KE, Ying AW, Turner AM, Jiang RJ, Raval S, So K, Allison MJ, Sankar A, Sáme Guerra DD, Lin Y, Jiang Z, Mashtalir N, Rohrs HW, Lichti CF, Muir TW, Papanastasiou M, Paulo JA, Gygi SP, Gross ML, Kadoch C. A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform. Science. 2026 Jan 1:eaeb3627. doi: 10.1126/science.aeb3627. Epub ahead of print. PMID: 41477818.

Featured image Dana Farber Cancer Institute. Courtesy © 2026 Dana-Farber Cancer Institute. used with permission.

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