A cell retains instructions on how to multiply and what type of cell to become when it divides. A previously unknown function for the SWI/SNF chromatin remodeling complex has been revealed by researchers at St. Jude Children’s Research Hospital, who have developed an entirely new understanding of how these processes can function. The study was published in Nature on May 24th, 2023.
Stem cells, which are the first cells to form, change through differentiation into a new type of cell, usually one with a more specialized purpose (such as a skin or muscle cell). To pass on the correct identity to the daughter cells, cells must maintain the “memory” of their current differentiation stage while they divide.
Inside cells, chromatin is a closely packed compound of DNA and protein. To activate and deactivate genes in tightly controlled processes, chromatin must unravel. By altering the chromatin architecture to govern gene expression, SWI/SNF complexes manage a cell’s identity throughout differentiation.
It is unclear, nevertheless, whether SWI/SNF complexes play a role in the memory of cell identity during cell division.
Mutations that alter the SWI/SNF chromatin remodeling complex are frequently seen in cancers. One instance is the disappearance of the core component SMARCB1. Neurodevelopmental problems and mutations in the complex have both been associated in other studies.
In this investigation, St. Jude researchers have uncovered how SWI/SNF subunits function as “bookmarks” during mitosis to protect cell identity throughout the division. The study emphasizes the significance of the SWI/SNF core subunits SMARCB1 and SMARCE1 and their functions in the procedure.
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.”
Charles W. M. Roberts, M.D, Ph.D., Study Senior Author and Director, Comprehensive Cancer Center, St. Jude Children’s Research Hospital
SWI/SNF Subunits Help Cells “Remember”
Until recently, scientists concluded that SWI/SNF complexes played no part in mitosis because they thought the enzymatically active component of the complex was not linked to DNA during this process.
Roberts stated, “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’ team discovered that only two of the SWI/SNF complexes’ individual subunits—not the complex as a whole—bind to mitotic DNA. They subsequently demonstrated that the proper reactivation of bound genes after mitosis depends on SMARCE1 and SMARCB1 binding.
In additional research, it was shown that the deletion of SMARCE1 affects gene expression, hinders the ability of several other “bookmarks” to bind to their targets, and results in aberrant neural differentiation.
These effects were caused by removing SMARCE1 during mitosis. According to these results, SMARCE1 functions as a mitotic bookmark and is crucial for preserving the proper differentiation programming throughout mitosis.
Roberts further stated, “In a normal cell, SMARCB1 would be bound in mitosis to bookmark the genes that should be turned on after the cell divides. 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 research revealed that 20% of all tumors had defective SWI/SNF subunits. Additionally, numerous other neurodevelopmental illnesses have been linked by studies to mutations in the SWI/SNF subunit.
“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. 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,” further added Roberts.
He concluded, “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. It is a beautiful model to understand how these processes work and then begin to leverage that understanding in adult cancers too.”
Zhu, Z., et al. (2023). Mitotic bookmarking by SWI/SNF subunits. Nature. doi.org/10.1038/s41586-023-06085-6