PLENARY LECTURER

On histones and glamour

allis award ceremony

C. David Allis accepts the Breakthrough Prize. Photos provided by David Allis

C. David Allis at Rockefeller University is an expert in chromatin, the complex formed between DNA and histones. His laboratory is interested in the post-translational modifications that occur on histones to remodel regions of chromatin into active and quiescent forms. Mutations in histones have been linked to several diseases, including a lethal form of pediatric cancer.

For his work on chromatin, Allis won the 2015 Breakthrough Prize, which is funded by Silicon Valley heavyweights including Sergey Brin of Google and Facebook’s Mark Zuckerberg. Rajendrani Mukhopadhyay, the science writer for the American Society for Biochemistry and Molecular Biology, spoke with Allis to learn more about his laboratory’s work and what it was like to rub shoulders with entertainment celebrities at the Breakthrough Prize ceremony. The interview has been edited for length and clarity.

C. David Allis

C. David Allis will give a plenary lecture at the American Society for Biochemistry and Molecular Biology annual meeting in Boston. He will present his lecture, titled “Beyond the double helix: varying the terrain of epigenetic landscapes in development and disease,” at 2:45 p.m. Tuesday, March 31, in Room 253 A/B/C of the Boston Convention & Exhibition Center.

What is your group working on right now?

One area is centered around what I nickname “oncohistones.” It is the pursuit of mechanisms that underlie some absolutely groundbreaking discoveries made at the end of 2012 and throughout 2013 by other groups that identified histone mutations in a pediatric cancer.

Histones are encoded by many copies of their genes. These researchers identified high-frequency point mutations in only one copy of only one allele of the genes that encode a particular histone.
In a (pediatric) brain-stem cancer, there is a point mutation in a histone. The mutation is most often a lysine-to-methionine (mutation). We can speculate all day — how can that one mutation be a problem when there are so many wild-type copies of the perfectly fine histones around? That’s been a puzzle. The point mutation acts like a poison that seems completely to inactivate the enzyme system that’s responsible for adding methyl groups (to histones).

Basic researchers like myself have been connecting with physicians who treat these devastating tumors. The goal is to learn more mechanistically about what’s going wrong with the hope that a therapeutic option might surface. These kids who get these brain-stem tumors often are in the age group of 5 to 10. They are often dead in six months to a year. Most all of them. It just can’t get more tragic in my book.
The other area we continue to be excited about is nonconventional post-translational modifications. We don’t discover them, necessarily; top-notch mass-spectrometry labs do that. We get excited about the enzymes that put on the modifications and ones that take them off. We like to nickname those kinds of enzymes “writers” and “erasers.” Post-translational modifications are read, so we like to call the proteins that do that “readers.” Then the $64,000-question is what does a post-translation modification do? Does it open chromatin? Does it close chromatin?

We’ve been putting a lot of energy into a modification that’s almost an acetyl lookalike. It happens to be two carbons longer, and it has one extra double bond. It’s called a crotonyl group. We can perturb cells with various genetic or environmental changes that cause the crotonyl-CoA ratio relative to acetyl-CoA to change. It seems you can reprogram the chromatin to switch from predominantly acetyl to predominantly crotonyl. Then you can jerry-rig the cells so it goes back to different acetyl marks.

How did you become interested in studying histones?

In my graduate program (at Indiana University), we had some strict requirements for seminars. I was pretty scared of them, so I put it off, put it off, put it off, because the professor who was in charge was known to be a real bulldog. Then (for my seminar), I picked this new topic on chromatin. It was one of those days when all of the stars aligned, and everything I said in my talk came out right. Feeling I had a really successful seminar, I got interested in the topic of chromatin.

It came time for me to graduate and pick a postdoc. I was going to stick with Drosophila, which was the organism that I chose for my Ph.D. work, but a postdoc in my Ph.D. lab got me to consider using Tetrahymena. It’s a ciliated protozoan. After doing some reading, what was cool about it to me was that it has two nuclei.

One nucleus is always silent. It doesn’t transcribe anything. In fact, you can suck that nucleus out with a micropipette, and the cell is just fine. What’s it doing? It turns out it’s the nucleus that plays a role in the next generation. The other nucleus is responsible for all the gene expression. It occurred to me that was nature’s gift for having essentially a pot of silent chromatin and a pot of active chromatin.

(Author’s note: The actively transcribing nucleus in Tetrahymena is called the macronucleus. The silent and smaller nucleus that goes into the germline is known as the micronucleus.)

There was the laboratory of Martin Gorovsky in Rochester, N.Y. He had worked out methods to separate the two nuclei. I made a commitment to leave Drosophila, go to his group and learn how to do this separation of nuclei. I decided to look at the histone proteins. There were big differences. The macronucleus had hyperacetylated histones.

When I started my own group as an assistant professor, I went after the enzyme system (that puts on the acetyl groups). A graduate student named Jim Brownell used the Tetrahymena macronucleus in 1996 as a starting point to purify this enzyme system. We published the study in Cell, and it was picked as a Cell Classic last summer.

What inspired you to become a scientist?

I don’t come from a science family at all. It was 100 percent decided for me that I would go to medical school. I gave it a crack for a couple of years. I had to do some moonlighting to pay bills. I was able to work for the Cincinnati coroner. He said to me, “You might want to rethink this whole thing about med school and consider science. Have you ever been in a real lab?”

I said, “I did chemistry.”

He said, “No, no, have you ever been in a real lab?” When he said it, it caused my heart to pause. He said, “I think you’re going to make a crummy physician. I think you’d be an amazing researcher. If you get interested, let me know. I have a friend in the med school who’s young and cool.”

I went to this person and interviewed. His name was Michael Bharier. He was at the Cincinnati medical school in the microbiology department. I took a leave of absence. (Bharier) took me under his wing and cut me loose on an enzyme.

I loved it. I brought all my medical school friends to show them the lab. My wife was like, “Oh, you’re kidding me. You’re going to do this?” Her family was especially crushed that I took this leave of absence. I just got hooked and never looked back. I enrolled in the Ph.D. program (at Indiana University) eventually. The rest is history.

What was it like to win the Breakthrough Prize in the life-sciences category?

They took us out to Silicon Valley. The star of the movie “The Imitation Game,” Benedict Cumberbatch, was at this ceremony. The main actor from “The Theory of Everything” was there as well. (Author’s note: It’s Eddie Redmayne.) At our table was Christina Aguilera. Talk about being a kid from Cincinnati who works on chromatin and histones … It was unbelievable.

award ceremony Aliis (center) at the Breakthrough Prize ceremony with Jon Hamm (right) and Lauren Powell Jobs (left).

The ceremony was done like the Academy Awards. The coolest thing for me was meeting Jon Hamm. He played Don Draper in “Mad Men.” My wife and I had become hooked on “Mad Men.” We didn’t know when we were out there who was going to be our introducer. You know you’ve won a prize, but you certainly don’t know who’s going to introduce you. Out comes Jon Hamm and Lauren Powell Jobs, Steve Jobs’ widow. They were the ones who did the whole spiel on me. It was ultracool. I also got to talk remotely with Stephen Hawking.

It was a hoot to meet all these stars. The fact that Jon Hamm and Lauren Powell Jobs were there, taking pictures with me, was a crack-up. And oh, the MC for the whole gala was Seth McFarlane.

With this prize, they are trying to show that science and mathematics are cool. They treat us as they would movie stars and sports people. I give these people a lot of credit.

Outside of the lab, do you have any hobbies?

I am embarrassed to say I haven’t yet put in a meaningful amount of energy outside of the lab. It’s becoming a family joke: “What’s Dad going to do if he retires?” That hasn’t been answered yet. Science is still my hobby. The motivation now is these oncohistone mutations that are killers in young kids. I feel like I can make a difference here.

What advice would you give younger scientists?

I’m an old guy. The thing that is most lacking now with the younger generation is everybody is hooked in their bubble. Everybody is on a device of some sort. I hope that young researchers get the thrill of science through direct one-on-one communication. Nothing is a bigger turn-on for me than meeting face to face with scientists. I really think the scientists who have good people skills, the ones who are willing to communicate openly and frequently, are the ones who do the best.

Rajendrani Mukhopadhyay Rajendrani Mukhopadhyay is the senior science writer and blogger for ASBMB. Follow her on Twitter, and read her ASBMB Today blog, Wild Types.