MSGID: 1:317/3 646ee47a   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    SWI/SNF complexes 'bookmark' cell identity during division    
      
     Date:   
         May 24, 2023   
     Source:   
         St. Jude Children's Research Hospital   
     Summary:   
         Scientists have determined how the SWI/SNF chromatin remodeling   
         complex helps cancer cells 'remember' how to be cancerous after   
         division.   
      
      
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   FULL STORY   
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   When a cell divides, it retains information about how to grow and   
   instructions about what type of cell to become. Scientists at St. Jude   
   Children's Research Hospital have gained a new understanding of how   
   these processes can work, revealing a previously unappreciated role for   
   the SWI/SNF chromatin remodeling complex. The study was published today   
   in Nature.   
      
   When a cell undergoes differentiation, stem cells (the earliest cells   
   that develop) undergo changes that transform them into a different type   
   of cell, typically one with a more specialized function (such as a skin   
   or muscle cell).   
      
   As cells divide, they must retain the "memory" of their current   
   differentiation state to transfer the proper identity to the daughter   
   cells.   
      
   Chromatin is a complex of DNA and protein tightly compacted inside cells.   
      
   Chromatin must unwind to turn genes on and off in closely regulated   
   processes.   
      
   SWI/SNF complexes control a cell's identity during differentiation by   
   changing chromatin architecture to regulate gene expression. However,   
   it was unknown whether SWI/SNF complexes contribute to the memory of   
   cell identity during cell division.   
      
   Cancers often carry mutations that affect the SWI/SNF chromatin remodeling   
   complex. One example is the loss of the core subunitSMARCB1. Other   
   studies have also linked mutations in the complex to neurodevelopmental   
   disorders. In this study, scientists at St. Jude have discovered how   
   subunits of SWI/SNF act as "bookmarks" during mitosis to safeguard cell   
   identity during division. The work points to the importance of SWI/SNF   
   core subunits SMARCE1 and SMARCB1and their roles in the process.   
      
   "This work provides an understanding of a new component of mitotic   
   memory, as well as provides clues to why a mutation of this SWI/SNF   
   complex subunit would disrupt memory of what a cell should normally be   
   doing and allow it to go into a cancerous state," said senior author   
   Charles W.M. Roberts, M.D., Ph.D., Executive Vice President and St. Jude   
   Comprehensive Cancer Center director.   
      
   SWI/SNF subunits help cells "remember" Previously, researchers believed   
   the enzymatically active subunit of the SWI/ SNF complex was not bound   
   to DNA in mitosis, so scientists have assumed that SWI/SNF complexes   
   had no role during mitosis. In launching this study, Roberts wondered,   
   "If a piece of this complex is mutated, how can a cancer cell remember   
   to be a cancer cell coming out on the other side of mitosis? What   
   is the memory mechanism sustaining the cancer cell?"  Surprisingly,   
   Roberts's team found that two individual subunits of SWI/SNF complexes,   
   but not the rest of the complex, bind to mitotic DNA. They then showed   
   that the binding of SMARCE1 and SMARCB1is required for the appropriate   
   reactivation of bound genes after mitosis.   
      
   Further experiments, which removed SMARCE1during mitosis, found that   
   loss of SMARCE1 disrupts gene expression, impairs the ability of some   
   other "bookmarks" to bind to their targets and causes abnormal neural   
   differentiation. These findings suggest that SMARCE1 plays a mitotic   
   bookmarking role and is essential for the retention of appropriate   
   differentiation programming during mitosis.   
      
   "In a normal cell, SMARCB1 would be bound in mitosis to bookmark the   
   genes that should be turned on after the cell divides," Roberts said. "But   
   SMARCB1 is deleted in nearly all cases of a highly lethal type of cancer   
   that strikes young children called rhabdoid tumors. Consequently cell   
   identity genes fail to turn on immediately after a cell divides. This   
   may be a key component that enables the cells to stay in a cancerous   
   state, as they fail to activate the genes that normally help them   
   differentiate."  Implications beyond pediatric cancer Previous work   
   showed that SWI/SNF subunit abnormalities exist in approximately 20%   
   of all cancers. Additionally, research has identified SWI/SNF subunit   
   mutations in several types of neurodevelopmental diseases.   
      
   "History has shown that genes that mutate in the earliest onset cancers,   
   in babies and toddlers, are often a bit of a 'canary in a coal mine'   
   for broader principles in cancer." Roberts said. "Indeed, while it was   
   studies of rhabdoid tumors in young children that first linked SWI/SNF   
   complexes to cancer, we now know that genes that encode subunits of   
   SWI/SNF complexes are mutated in 20% of all cancers. Studying rhabdoid   
   tumors, thus, not only provides insight into these often fatal cancers   
   of young children, it is quite informative about many types of cancer."   
   "Unlike adult cancers, where many genes are mutated, and it is harder   
   to figure out what any single abnormality does, here we have a cancer   
   driven by just this one mutation," Roberts added. "It's a beautiful model   
   to understand how these processes work and then begin to leverage that   
   understanding in adult cancers too."  Authors and funding The study's   
   co-first and co-corresponding author is Zhexin Zhu, formerly of the   
   St. Jude Department of Oncology. The other co-first author is Xiaolong   
   Chen, St. Jude Department of Computational Biology. Other authors are   
   Ao Guo, Trishabelle Manzano, Patrick Walsh, Kendall Wills, Rebecca   
   Halliburton, Sandi Radko-Juettner, Raymond Carter, Janet Partridge,   
   Douglas Green and Jinghui Zhang of St. Jude.   
      
   The work was part of the St. Jude Collaborative Research Consortium on   
   Chromatin Regulation in Pediatric Cancer. Through the collaborative,   
   investigators at different institutions conduct research that requires   
   the expertise of scientists with various specialties, streamlining and   
   speeding up progress.   
      
   The study was also supported by the National Institutes of Health   
   (R01CA216391, R01 AI123322), the National Cancer Institute (NCI) Cancer   
   Center Support Grant (CCSG 2 P30 CA021765), NCI grants (R01CA113794   
   and R01CA172152), CURE AT/RT Now, Garret B. Smith Foundation, the Ruth   
   L. Kirschstein National Research Service Award (F31 CA261150) and ALSAC,   
   the fundraising and awareness organization of St. Jude.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Brain_Tumor # Cancer # Lung_Cancer # Stem_Cells #   
                   Lymphoma # Breast_Cancer # Skin_Cancer # Colon_Cancer   
       * RELATED_TERMS   
             o Colorectal_cancer o Cancer o Prostate_cancer o Chemotherapy   
             o Mesothelioma o BRCA1 o Isoflavone o Pap_smear   
      
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   Story Source: Materials provided by   
   St._Jude_Children's_Research_Hospital. Note: Content may be edited for   
   style and length.   
      
      
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   Journal Reference:   
      1. Zhexin Zhu, Xiaolong Chen, Ao Guo, Trishabelle Manzano, Patrick   
      J. Walsh,   
         Kendall M. Wills, Rebecca Halliburton, Sandi Radko-Juettner,   
         Raymond D.   
      
         Carter, Janet F. Partridge, Douglas R. Green, Jinghui Zhang,   
         Charles W.   
      
         M. Roberts. Mitotic bookmarking by SWI/SNF subunits. Nature, 2023;   
         DOI: 10.1038/s41586-023-06085-6   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230524181853.htm   
      
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