How Cell Identity is Preserved When Cells Divide
Published:30 Jan.2024 Source:Massachusetts Institute of Technology
A new MIT study proposes a theoretical model that helps explain how these memories are passed from generation to generation when cells divide. The research team suggests that within each cell's nucleus, the 3D folding pattern of its genome determines which parts of the genome will be marked by these chemical modifications. After a cell copies its DNA, the marks are partially lost, but the 3D folding allows each daughter cell to easily restore the chemical marks needed to maintain its identity. And each time a cell divides, chemical marks allow a cell to restore its 3D folding of its genome. This way, by juggling the memory between 3D folding and the marks, the memory can be preserved over hundreds of cell divisions.
Previous work by Mirny's lab has shown that the 3D structure of folded chromosomes is partly determined by these epigenetic modifications, or marks. In particular, they found that certain chromatin regions, with marks telling cells not to read a particular segment of DNA, attract each other and form dense clumps called heterochromatin, which are difficult for the cell to access. When a cell copies its DNA to divide it between two daughter cells, each copy gets about half of the epigenetic marks. The cell then needs to restore the lost marks before the DNA is passed to the daughter cells, and the way chromosomes were folded serves as a blueprint for where these remaining marks should go. There are several lines of evidence that suggest that the spreading can happen in 3D, meaning if there are two parts that are near each other in space, even if they're not adjacent along the DNA, then spreading can happen from one to another.
This process is analogous to the spread of infectious disease, as the more contacts that a chromatin region has with other regions, the more likely it is to be modified, just as an individual who is susceptible to a particular disease is more likely to become infected as their number of contacts increases. Broadly this suggests that akin to the way neural networks are able to do very complex information processing, the epigenetic memory mechanism we described may be able to process information, not only store it. To get the model to more accurately account for the preservation of epigenetic marks, the researchers added another element: limiting the amount of reader-writer enzyme available. They found that if the amount of enzyme was kept between 0.1 and 1 percent of the number of histones (a percentage based on estimates of the actual abundance of these enzymes), their model cells could accurately maintain their epigenetic memory for up to hundreds of generations, depending on the complexity of the epigenetic pattern.