Dr. Toshio Tsukiyama elected to American Academy of Microbiology

Unlike bacteria, eukaryotes (which include humans and yeast) separate their DNA from the rest of the cell’s inner workings by storing it in the nucleus. A human cell’s nucleus holds two meters, or nearly six-and-a-half feet, of DNA.

“If the nucleus were the size of a grapefruit — about four inches in diameter — the length of DNA inside it would be something like 12 miles,” Tsukiyama said. “So the level of compaction that the DNA has to undergo to fit inside the nucleus is just enormous.”

But a cell can’t just stuff DNA inside its nucleus willy-nilly. It must keep its DNA organized enough that it can access the genes it needs to work properly. That set of genes will differ by cell type and cell state. Cells from yeast to human have evolved a suite of proteins that help compact DNA, and tighten or loosen this compaction to enable (or inhibit) gene expression.

Which regions are tighter or looser can change rapidly as cells move between different cell states, as when a cell moves from a non-dividing into one that allows it to turn on new genes and duplicate its DNA as it prepares to divide in two.

But when Tsukiyama began studying chromatin, this changeability was unrecognized, he said: “They thought it was just a ‘brick’ you need to have to store genetic information.”

Many scientists found chromatin about as interesting as a brick, too. Scientists focusing on chromatin were few and far between. The few who did found themselves relegated to little-attended corners of scientific conferences. Tsukiyama helped the field reevaluate.

He received a doctorate of veterinary medicine from Obihiro University and his PhD from Hiroshima University in Japan. Tsukiyama then joined the National Cancer Institute in Bethesda, MD, for his postdoctoral work. There, he discovered a chromatin-remodeling factor that uses adenosine triphosphate, or ATP, the molecular “gasoline” that powers our enzymes.

In other words, he showed that chromatin changes result from an active, not passive, process.

“This groundbreaking discovery helped usher in the recognition that chromatin architecture is dynamic and that defects in this process play an important role in gene expression and human disease,” Hahn said in his nomination letter.

Early in his career at Fred Hutch, Tsukiyama studied other chromatin remodeling factors and helped show how they work. The most basic unit of DNA packaging is the nucleosome, a wagon wheel-shaped complex around which DNA wraps like yarn around a spool. The more nucleosomes a stretch of DNA wraps around, the tighter, more compact and harder to access it becomes. Tsukiyama demonstrated, for the first time, that a chromatin-remodeling protein called Isw2 can alter chromatin by sliding nucleosomes along DNA.

A major function of chromatin is to control gene transcription, but Tsukiyama revealed that chromatin remodelers play other important roles. He found that the nucleosome-sliding protein Isw2 collaborates with another protein to control the replication of DNA during cell division. Tsukiyama also discovered that these proteins regulate the number of copies of the genetic code for ribosomal RNA, an essential component of a cell’s protein-making machinery.

About 15 years ago, he teamed up with Fred Hutch geneticist Linda Breeden, PhD, to study quiescence, a dormant state that protects cells from stressors like extreme temperatures or lack of food.

“We immediately realized what an interesting system it is, because chromatin undergoes a huge transition,” Tsukiyama said.

When yeast cells enter quiescence, they turn off most genes and stringently compact their DNA, shrinking their nuclei by 40%. Levels of RNA, the precursor molecule to protein, are 15-30 times lower than in actively dividing cells.

Quiescence is also important in human health and disease.

Skin stem cells lie dormant until they need to “wake up” and produce more skin cells to heal a wound. In cancer, quiescence helps some tumor cells withstand chemotherapies that kill off fast-dividing cells, leaving them free to seed new tumors.

It didn’t take long for Tsukiyama to go all-in on studying quiescence and the incredible wide-scale chromatin changes that occur as the dormant state is built and then dismantled. He revealed the extent of gene shut down and chromatin compaction that occurs in quiescence. His team also showed how chromatin modulators help regulate entry into quiescence and demonstrated that a protein called condensin helps ensure gene repression in large loops of DNA.

Tsukiyama has also shed light on how “sleeping” cells can move out of quiescence, which happens at an amazing speed, he said.

“Quiescence is formed over seven days [as food levels decline], and then the yeast can live for a long, long time,” he said. “But you drop them in rich media, and within 30 minutes, RNA levels are as high or higher than before quiescence.”

His work has also revealed the molecules, including condensin, that help quiescence cells roar back to life.

“This election is fantastic recognition of Toshi’s important contributions to the chromatin field throughout his career. It is also wonderful to see a colleague who has dedicated so much time to mentoring and service to Fred Hutch be rewarded for his scientific achievements,” said Basic Sciences Division Director Sue Biggins, PhD.

Tsukiyama said he is also very proud of the careers his mentees have built for themselves, many establishing their own academic research groups. He has also extended his mentorship activities beyond his own team, teaching graduate students nearly every year and organizing a biannual graduate course on chromatin and gene transcription.

And he's stayed at the forefront of technology in a technology-driven field.

When Tsukiyama joined Fred Hutch, he was interested in a broad-scale view of genes and chromatin: the genome, or full collection of genes in an organism. The word genomics (and the many ‘omics’ to come) had yet to be coined, but Tsukiyama helped bring early genomic techniques to Fred Hutch and worked to stay at the forefront of innovations that can help us understand chromatin’s structure and function.

Technology is still showing how much there is to learn about how cells organize DNA. New super-resolution microscopes and genomics technologies have revealed that certain chromatin structures scientists saw in extracted chromatin can’t be found inside cells.

“This highlights how little is still known about how our genetic information is stored inside the nucleus,” Tsukiyama said. “It’s a fundamental issue, especially given that mutations in many regulators of chromatin structure have been linked to many diseases, including cancer.”

He’s honored by the recognition of his colleagues, he said.

“It was really nice feeling to hear that the people who I respect actually did a lot of work for me,” Tsukiyama said. “To know that they think I deserve this is very humbling.”

Tsukiyama was among 65 fellows elected to AAM this year, and joins Fred Hutch colleagues Hahn, Robert Eisenman, PhD, Michael Emerman, PhD, Denise Galloway, PhD, Harmit Malik, PhD, Nina Salama, PhD, and Gerald Smith, PhD. Galloway holds the Paul Stephanus Memorial Endowed Chair and Salama holds the Dr. Penny E. Petersen Memorial Chair for Lymphoma Research.