To Be or Not to Be

Epigenetics explains the fate of baby cells. But what happens when cells grow up?

Every cell in the human body contains the same set of genes. But only some of those genes are turned on — or expressed — in any specific cell. Cardiac cells turn on genes required for heart function, for example, while kidney cells express a different set of genes.

Each cell’s unique pattern of gene expression is fixed early in an embryo’s development. But how do cells maintain their genetic identity over time?

In a new field of science called epigenetics, researchers are exploring how cells know which genes to express. Each cell stores coded instructions for all its genes on long strands of DNA packed into tight bundles called histones. Genes can only be expressed if these bundles relax and unwind the DNA, allowing the genetic instructions inside to be copied and transferred from the nucleus to other parts of the cell. If certain biochemical tags are attached to a section of DNA, the histone will relax and those genes can be expressed. But if different biochemical tags are attached, the DNA remains tightly spooled and those genes stay silent.

Gregory Dressler, Ph.D., the Collegiate Professor of Pathology Research, and Adam Stein, M.D., an assistant professor of internal medicine, wanted to know if the biochemical signals that control histone relaxation were important to adult cells. So Dressler and Stein, a cardiologist, decided to study their effects on heart muscle cells called cardiomyocytes in adult mice.

Dressler studies kidney development and has spent years working with proteins called H3K4 methyltransferases, which mark genes to be expressed during embryonic development.

To change the normal pattern of histone methylation tags in heart muscle cells, the U-M scientists knocked-out one gene in the H3K4 methyltransferase complex of a strain of research mice and then examined the effects on cardiomyocytes and heart function.

“We found that epigenetic imprinting controlled the expression of genes important for normal heart equilibrium,” says Stein. “Without normal histone methylation, adult mice developed altered potassium channel activity and electrical instability in their cardiac cells. We can’t say that defects in histone methylation caused these cardiac arrhythmias, but it’s a potential causative factor.”

The study was the first to recognize a potential link between defective epigenetic imprinting and heart disease in animals. Previously, Dressler discovered an epigenetic connection to defects in kidney cells. The bottom line is that “epigenetic changes can alter the properties of adult cells in ways that can lead to disease,” Dressler says.

In future research, Stein hopes to determine whether mutant methylation affects how the heart responds to stress. Dressler plans to explore how a cell’s epigenetic imprint affects how it responds to developmental signals. —SALLY POBOJEWSKI

Read the published study

 

MacArthur Calling

When Yukiko Yamashita, Ph.D., answered the phone recently, she had no idea her life was about to change. “Someone you know very well just got a MacArthur award,” said a voice on the other end of the line. “Can you guess who it is?”

“I kept saying ‘I don’t know,’ ” says Yamashita, an assistant professor of cell and developmental biology. “Finally, they said it was me. I couldn’t believe it.” She called her husband who warned: “If you get another call asking for your bank account and PIN number, don’t give it to them!”

It’s not every day that a young scientist just starting her career gets $500,000 to spend however she wants. MacArthur award winners are always surprised, because no one ever applies for a fellowship and the selection process is conducted in total secrecy. Recipients are chosen for their “creativity, originality and potential to make important contributions to the future,” according to MacArthur Foundation officials.

Yamashita is one of 22 MacArthur winners for 2011, and one of 24 U-M faculty members who have received awards since the program was established in 1981.

She says she will use the $500,000 to explore results from her research that are unexpected and point in an important new direction.

Yamashita is a stem cell biologist who joined the U-M faculty in January 2007 after completing a postdoctoral fellowship at Stanford University. She studies how adult stem cells in the reproductive tracts of male fruit flies divide to form one stem cell and one daughter cell that becomes a sperm. She focuses on centrosomes — structures that help cells form a division apparatus, or spindle, during cell division. If centrosomes don’t line up properly, mitosis can’t proceed normally in these stem cells. As fruit flies get older, centrosome misalignments become more common, which could explain why sperm production declines with age. —SP

More about Yukiko Yamishita
More about Yamashita’s research

 

A Molecular Switch in Action

Cells do it millions of times every day: A protein called a G protein-coupled receptor (GPCR) embedded in the cell’s outer membrane detects an incoming signal — such as a hormone or neurotransmitter, from outside the cell. Grabbing hold of the signal, the GPCR latches onto another protein inside the cell membrane to create a molecular switch, which activates a specific intracellular response.

Exactly how does this molecular switch work? Biologists and biochemists have been trying to figure it out for decades. Now, three teams of scientists — led by researchers at the U-M, the University of California, San Diego and Stanford University — have taken a major step toward solving the puzzle.

In papers featured on the cover of Nature, the international research collaboration published the first high-resolution images showing the molecular structure of a G protein-coupled receptor caught in the act of binding to a G protein inside the cell.

Virtually every type of cell activity depends on these molecular switches. Without them, cells couldn’t respond to changes in their environment. Hearts would stop beating. Nerves would stop firing. It would be impossible to see, hear or smell.

Defects in the GPCR signaling complex have been linked to many diseases. Nearly half of all therapeutic drugs are designed to target different GPCRs. But drug discovery has been limited by an incomplete understanding of exactly how the complex works.

“Now we know how the signaling complex is assembled and how the receptor turns G proteins on,” says Roger Sunahara, Ph.D., an associate professor of pharmacology who led one of the research teams. “This will help scientists design new and more effective drugs.” —SP

An expanded version of the story