When cells divide, they do not merely replicate the genome. The molecules bound to the genome define the cell’s function and must also be replicated; otherwise, diseases such as cancer can develop. This extremely complex mechanism has been almost impossible to characterize, but researchers have now discovered a key to understanding the process. Just one error in a protein entirely ruins the copying process. This discovery could be decisive in understanding cell fate decisions in development.
The human body comprises more than 200 known types of cells, each with its own function. The cells contain exactly the same genetic code but differ based on the epigenetic signature. For example, methyl groups can bind to the DNA and thereby silence genes. Similarly, proteins called histones package our metre-long chromosomes and ensure that genes, including the cell type–specific ones, are correctly regulated. When cells divide, this information must be passed on to the new daughter cells.
“The epigenetic signature can be viewed as a cell’s memory. Until now, we have known in detail how the genome is replicated, but it has remained unknown how the epigenome is replicated. Our latest study reveals how histones, building blocks of the cellular memory, are transferred when a cell divides. We have shown that the MCM2 protein is key for transferring these building blocks and thus propagating epigenetic cell memory. This breakthrough will be instrumental to fully understanding cell memory, a fundamental biological process important for developing a healthy organism that counteracts diseases such as cancer,” explains Anja Groth, Professor, Biotech Research & Innovation Center, University of Copenhagen.
Tiny change with big effects
A pioneering new technique has enabled the researchers to identify the protein that ensures that histones are inherited when cells divide. The new technique, sister chromatids after replication (SCAR) sequencing, enables researchers to track proteins bound to the two new DNA strands created when DNA is replicated. Using this technology, the researchers identified a key role for the protein MCM2 in distributing histones and the information they carry to both DNA daughter strands.
“This provides the first direct evidence that a specific protein is directly linked to transmitting histone-based information and thus replicating the cell’s epigenetic profile, which constitutes the memory about what type of cell it is.”
The experiments showed that MCM2 is responsible for correctly distributing histones during DNA replication, ensuring that they are transferred to the new cells. Histones and the genome create a structure called chromatin, and this structure helps cells to maintain the correct functions.
“MCM2 is therefore directly linked to the replication of histone-based information. When we mutated MCM2 so that it could no longer bind histones, the histones were no longer distributed to both DNA strands. This provides us with a unique system to investigate what happens with cell memory and organismal development when the inheritance of information in histones is disrupted.”
Unlocking many new opportunities
Because many cells in the human body divide throughout life, it is critical to understand how they remember what they are and whether they should give rise to skin, liver or intestinal cells. This is important for developing and maintaining a healthy organism and to avoid diseases such as cancer. However, the mechanisms that govern epigenetic cellular memory are unclear, and this continues to perplex researchers.
A recurring question has been the extent to which the chemically modified histones are randomly transferred during DNA replication. Our study shows that this process is tightly controlled and not random. With our new knowledge and uniquely engineered cells, we can begin to examine exactly how the inheritance of this information affects cells and the development of whole organisms.
This new ability to block the proper handling of histones enables the researchers to determine exactly how important histone inheritance is for developing a complete organism from a single cell: that is, whether disturbing the function of MCM2 influences the ability to create other types of cells.
“Researchers often discuss how important the information histone contains really is for a cell’s identity and fate. This discovery enables us to start new experiments that may finally answer this question. So this is an incredibly important key to unlocking many longstanding enigmas.”
This new understanding of a key mechanism in histone inheritance provides new opportunities within stem cell research and regenerative medicine, such as taking skin cells from people and reprogramming them. It can also help understanding how perturbing cell fate contributes to cancer.
When cancer develops, cells change their identity and obtain unwarranted properties. The fact that cells remember what type they are and thereby their function helps to prevent them from developing undesirable characteristics such as dividing unimpeded, which cancerous cells do. We know that cancer cells suffer pervasive changes in chromatin, and it will be exciting to investigate how impaired transmission of histones influences cancer predisposition.
“MCM2 promotes symmetric inheritance of modified histones during DNA replication” has been published in Science. The research was funded by the Independent Research Fund Denmark, the European Research Council, the Lundbeck Foundation and the Novo Nordisk Foundation.