The molecular world that exists within our cells is constantly changing as cells adapt to the complex environment within our bodies. Wistar researchers work to unravel this confusing tangle of molecules, in order to understand how disease begins on a molecular level—and to develop new drugs for diseases such as cancer.
Our cells have evolved a remarkable molecular trick to modify how its proteins work by tagging them with a special molecule in a process called “acetylation.”
Within the confines of our cells is an amazing molecular world that regulates everything from our genes to how cells grow and divide. It is a place that is not run with clockwork precision, as you might expect, but with a remarkable degree of flexibility and adaptability. This plasticity keeps things working in response to the ever-changing conditions within our bodies. When it goes wrong, however, it can lead to diseases, including cancer.
With modern laboratory technologies, scientists at The Wistar Institute are piecing together the many ways the molecules within our cells operate in states of both health and disease.
One growing field of studies involves examining the role of a process called “acetylation” in modifying how proteins work and, by extension, how cells can adapt to changes in their immediate environment. In acetylation, enzymes within the cell will modify or “tag” other proteins with a small compound called an acetyl group. The acetyl group—a tiny twig of a molecular fragment comprised of just six atoms—can dramatically change the activity of a protein and how other proteins interact with it.
Two recent studies from Wistar scientists demonstrate the remarkable role of acetylation in the molecular lives of our cells.
Broadening the Acetylome
For many years, the laboratory of Wistar’s Ronen Marmorstein, Ph.D., has studied the structure and role of enzymes that modify histones, proteins that form large complexes around which DNA is wound. Histone acetylation can change how certain genes are expressed—or read—by the cell. Marmorstein and his colleagues have shown how these enzymes can have a dramatic effect on the health of cells, and might provide a therapeutic target in treating some diseases, including forms of cancer.
Recently, in the Proceedings of the National Academies of Science, Marmorstein and his colleagues published the first molecular structure of an enzyme that acetylates proteins outside of the cell nucleus. This enzyme, called tubulin acetyltransferase (the acetlytransferase literally transfers acetyl groups to tubuin), was independently discovered just two years ago by scientists at the University of Georgia and Stanford University. Marmorstein collaborated with the Stanford group on this study. The enzyme modifies parts of microtubules—the rod-like cluster of proteins that form the supporting skeleton of cells.
[In the image above: Molecular structure of tubulin acetyltransferase (TAT1) against a background image of a cell whose acetylated microtubules have been stained black.]
By adding an acetyl group to microtubules, the enzyme can alter the stability and activity of microtubules—and thus the vast array of proteins that rely on microtubules in order to function properly.
“Solving the structure of this tubulin acetyltransferase is a first step in solving the larger puzzle of how all these different acetyltransferase enzymes coordinate functions in cells,” said Marmorstein, Wistar’s Hilary Koprowski, M.D., Professor and leader of Wistar’s Gene Expression and Regulation Program. “Knowing the structure of this enzyme also provides inroads to create drugs that inhibit it, which could be a method to help, for example, current cancer drugs that kill tumors by targeting microtubules.”
Their studies showed that tubulin acetyltransferase shares many basic similarities with the histone acetyltransferases that regulate gene expression, although each type of enzyme is suited to better interact with their respective target proteins—namely microtubulules and histones. Marmorstein believes that the discovery and characterization of tubulin acetyltransferase is an important step in the discovery of more cases of acetylation throughout the cell.
According to Marmorstein, the “acetylome” is the latest in the emerging body of knowledge often simply called “omics.” First came the study of the full complement of genes written into our DNA, the “genome,” followed by the cataloging of proteins that our cells produce, the so-called “proteome.” As scientists catalog the omes, they move closer to using omic information to detect disease or create new and more effective drug therapies.
With the discovery that the acetylome extends beyond the confines of the nucleus and the DNA it contains, it is quite likely a larger portion of the cell’s molecular ecosystem that is affected by enzymes that change how proteins work by modifying them.
“Microtubules are incredibly important to cell function, from providing a physical scaffolding for protein complexes to form to helping separate the replicated DNA into daughter cells in cell division,” said Marmorstein. “The notion that acetylation can also drive microtubule regulation in addition to genetic regulation is outstanding, but it pales in front of the larger idea of how many other systems within our cells are affected by acetyltransferases or related forms of modification.”
Acetlyation Helps Bring the Genome Together
In 2010, Wistar’s Ken-ichi Noma, Ph.D., published a remarkable observation about the genome. The very structure of the genome itself serves a purpose. That is, the three-dimensional form that the genome takes on helps regulate how genes are read. (In his work, the fission yeast genome, but the lesson likely applies to all genomes.)
While most people are familiar with the little X-like shapes of chromosomes, many people might be surprised to learn that our DNA only takes this form for a relatively short amount of time as cells replicate their DNA and divide into two new (“daughter”) cells. For the rest of the cell’s life cycle, our DNA sits in what appears to be a shapeless tangle of thread.
According to Noma, evidence shows that the three-dimensional structure of the genome can determine how available, physically, genes are to the molecular complexes that read genes and translate DNA sequences into proteins and other products. Aberrations in this structure could, for example, cause genes to be poorly read or misread in some way, leading to disease.
This November, in the journal Molecular Cell, Noma publishes the results of experimentation that further refines this notion. Noma has found that acetylation might further dictate the shape of the 3-D structure of the fission yeast genome (which have just three individual chromosomes compared to the 23 pairs of chromosomes in humans, and are, thus, easier to study).
[In the diagram: A schematic model for retrotransposon-mediated genome organization and its regulatory mechanism through histone H3K56 acetylation.]
The Noma laboratory shows that the clustering of chromosomes is dictated by large molecular complexes that form at the ends of chromosomes and along certain segments of DNA in the middle of chromosomes, called centromeres. Their studies show that acetylation of histones within this big ball of DNA can change the 3-D structure of the genome by physically separating the points at which different chromosomes attach to each other.
Their study showed, for example, how acetylation of one particular amino acid on one histone protein (called H3K56)—which is necessary for copying (or replicating) the DNA in advance of cell division and also DNA repair—dictates the 3-D structure of the genome.
“Our study reveals for the first time that a specific histone modification directly governs global genome organization,” said Noma, an assistant professor in Wistar’s Gene Expression and Regulation program. “We hope to use the lessons learned here in our effort to model the three-dimensional structure of the human genome, offering deeper insight into genetic regulation.”