How does the same DNA result in more than 200 different cell types?

Every human body starts out as one single cell: a fertilized egg. This cell develops into all kinds of cell types: skin cells, liver cells, blood cells... Although these cell types look and function differently, they all contain exactly the same DNA. Tuncay Baubec and his research group try to understand how the same genetic code is used to build the more than 200 different cell types in our body. By zooming in on mechanisms that chemically modify DNA without changing the actual DNA sequence, they want to figure out how genes are turned ‘on’ and ‘off’ at the right time during development. Besides leading to fundamental insights into these mechanisms, results of this research might also have implications for cancer therapy.

Approximately 25 000 genes, regions of DNA that are ultimately translated into proteins, are present in our genetic code. But within a cell, only one third to one half of these genes are active at the same time. Depending on which genes are active at specific times during the development of a cell, the cell develops into a certain cell type. Baubec: “We want to know more about how these genes are regulated. How are the right genes turned ‘on’ and ‘off’ at the right time, giving rise to certain cell identities?”

Gene regulation

Various mechanisms are known to influence the activity of genes without affecting the sequence of the DNA itself. For example, our entire genetic code is packaged into chromatin, a mixture of DNA and proteins. This packaging influences how transcription factors, proteins that control the activity of genes, interact with those genes. On top of that, there are several kinds of chemical modifications of the DNA that influence how these transcription factors switch genes on and off. One example of such a modification is DNA methylation, a process by which chemical structures called methyl groups are added to certain regions in the DNA. A gene that is methylated, is often deactivated.

Inherited modifications

Modifications like DNA methylation can work as a memory mechanism: once DNA is methylated at a certain location, the modification can be memorized and inherited during cell division. This helps to ensure that the identify of a cell is correctly passed on after every division.

The field of study that looks at altered traits that are inherited without changes in the DNA sequence, is called epigenetics. Epigenetic modifications can potentially be transmitted from parents to their offspring, such that certain traits that are not stored in the sequence of the DNA are inherited from one generation to the next. Baubec: “Multigenerational inheritance through epigenetic modifications has been shown in plants. But in mammals, for instance humans and mice, evidence is not yet convincing.”

Genomic imprinting

Yet it is clear that epigenetic modifications do play an important role during the development of individual mammals, including humans. One well known example of this is a mechanism called genomic imprinting. In genomic imprinting, genes are methylated depending on whether they come from the mother or the father.

Each cell contains two copies of each gene, one from the father and one from the mother. Such a copy of a gene is called an allele. Due to genomic imprinting, only one of those two alleles is turned on, while the copy from the other parent is turned off. At least 100 genes in our DNA are affected by genomic imprinting, many of which play a role during development.

Once an imprinted allele is turned on or off in a sperm cell or egg cell, this allele remains in the same state during the entire development of the offspring that results from the fusion of the sperm and egg cell. Even though genes that are affected by genomic imprinting do not play a role in cell differentiation, Baubec is very interested in the mechanisms behind genomic imprinting. Baubec: ”Imprinted genes are unique examples of epigenetic gene regulation. You have the same identical sequence in two different states in the same cell. By systematically studying this, we can learn how epigenetic modifications can turn genes on and off.”

Recent publication

Even though DNA methylation potentially can turn a gene off, this does not necessarily mean that all methylated genes are deactivated, or that the methylation is memorized during cell division. In genetic regions that are affected by genomic imprinting, however, DNA methylation does result in a deactivation that is memorized during many cell divisions. In a recent scientific publication, Baubec and his team elucidate some of the characteristics of imprinted DNA regions that allow them to be turned on or off via methylation.

They identified features of the DNA sequences of these regions that were required for the maintenance of epigenetic states. Baubec: “We changed the sequence, we cut it into smaller pieces. By doing so, we were able to identify what makes it respond to methylation and what makes it stop responding.” Baubec and his team also were able to identify proteins that regulate the epigenetic memory.

Babysteps

The research on genomic imprinting is just one of many projects that run in his lab. It is a good example of how the group’s approaches their research. Baubec: “We like to simplify things. The way genes are regulated is extremely complex. There are many factors that play a role, like the characteristics of the DNA sequence and many proteins. These factors influence each other in ways that we might not even know.”

Mechanisms in biology are just not very smart.

Baubec tries to break the complex reality down to smaller pieces, to be able to first understand what these factors are. Baubec: “If you do not do that, you can get completely lost in the multidimensional space of all these factors that interact and feedback. By taking baby steps, we can start playing around by combining the small pieces and trying to reconstitute what we observe in real life.”

According to Baubec, this approach is the result of a larger challenge in biological research. Baubec: “Mechanisms in biology are just not very smart. In evolution, whatever works, works. And once it works, it is locked in. This is not something that we as scientists can really grasp. It works against our way of logic.”

Implications for cancer research

The research on imprinted genes is fundamental, focusing on the basic understanding of how epigenetic mechanisms work. Yet, results might have implications for cancer research. Baubec: “In cancer, genes that suppress tumors are often methylated. So it might be that the cancer is caused because the methylation has turned off the suppressor, leading to tumors. There are techniques to remove the DNA methylation at specific sites by using enzymes. But we know that methylation does not always turn a gene off, and just removing the methylation often does not turn a gene back on. Knowledge from our research will help to target tumor suppressor genes where the methylation has actually turned off the gene. This will save a lot of time finding the right genes to target for this kind of therapy.”