The SWI/SNF Ig-Fold for Transcription Factor Interactions or 'SWIFT' domain on mSWI/SNF chromatin remodeling complexes engage proteins called transcription factors (TFs) to target specialized genes along human DNA-often cancer-promoting genes-flagging SWIFT-TF interactions as promising new therapeutic targets.
Precision and timing of gene expression is 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 discovered a new protein domain, SWIFT, found on a major chromatin remodeling complex family called mammalian SWI/SNF (mSWI/SNF or BAF) complexes, which helps these regulatory machines target particular genes to activate their expression.
The findings, published in Science, reveal how the SWIFT platform on mSWI/SNF complexes engage 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, breaking interactions with mutations halts cancer cell growth, flagging this new SWIFT-TF platform as a promising target for small molecule development.
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 Dr. Cigall Kadoch, 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 said. "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."
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 different collections of TFs, a new learning from this work that explains the reasons behind SMARCD tissue specificity and supports opportunities for therapeutic disruption of 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."
In blood cancers, such as acute myeloid leukemia, 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," said Dr. Siddhant Jain, the study's first author and a Dana-Faber postdoctoral fellow. "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."
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.
"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 says.
Co-authors of the study are: Alexander Ying, BS, Kaylyn Williamson, PhD, Aasha Turner, BA, Akshay Sankar, BS, Daniel Sáme Guerra, PhD candidate, Kevin So, PhD candidate, Maxwell Allison, PhD candidate, and Nazar Mashtalir, PhD, of Dana-Farber; Jerry Jiang, PhD, Malvina Papanastasiou, PhD, and Shaunak Raval, PhD, of the Broad Institute of MIT and Harvard; Joao Paulo, PhD, and Steven Gygi, PhD, of Harvard Medical School; Cheryl Lichti, PhD, Henry Rohrs, PhD, Michael Gross, PhD, and Ruidong Jiang, PhD, of Washington University in St. Louis; Tom Muir, PhD, Yutong Lin, PhD, and Zhe Jiang, PhD candidate, of Princeton University.
Funding for this study was provided by: National Institutes of Health, Pew-Stewart Scholars Program in Cancer Research, American Cancer Society Research Scholar Program, The Mark Foundation for Cancer Research Emerging Leader Program, The Gabrielle's Angel Foundation, The Howard Hughes Medical Institute, AACR Basic Science Fellowship and the National Science Foundation Graduate Research Fellowship Program.
