Five Questions for Brad Bernstein

Haley Bridger, August 23rd, 2010 | Filed under

Earlier this month, researchers from the Broad Institute and Massachusetts General Hospital (MGH) published a paper in Nature Methods about a new approach to an established technique. The technique is called ChiP-seq, short for chromatin immunoprecipitation with high-throughput sequencing, and is used to study how protein and DNA interact. The paper's authors are postdoctoral scholars Mazhar Adli and Jiang Zhu and Broad associate member Brad Bernstein. Brad answered five of our questions about his latest paper and his field of interest.

Brad is as an associate professor of pathology at MGH and Harvard Medical School. His work is in the field of epigenomics, which literally translates to the study of what’s “on top of” the genome. Epigenomics looks beyond our DNA sequence at the inherited factors that change our genetic instructions. Epigenomics helps answer such fundamental questions as how the same genetic material contained in all of our cells can give rise to so many different cell types (neurons, red blood cells, ganglion cells, etc.). The key difference may be the way DNA is organized inside the cell, preventing or allowing certain regions of the genetic code to be read and therefore expressed.

Brad moved to Boston from the West Coast in 1999 to complete his post-doc in the lab of Broad Institute core member Stuart Schreiber. Today, Brad studies the role of chromatin – the structure of tightly packed DNA and proteins that makes up chromosomes – in epigenetics and development. In addition to the paper on ChiP-seq, Brad recently published a paper on pediatric kidney tumor cells (you can read a recent Broad news story on the research here).

Q1: You had a paper come out in Nature Methods earlier this month about a sequencing technique, ChiP-seq, that usually requires large amounts of starting materials. You and your team developed a way of performing this technique using a limited number of cells. Why is this important?

Brad: ChiP-seq has increasingly become the go-to method for profiling chromatin structure or transcription factor binding across the genome. Its value lies in its comprehensive and unbiased nature. However, it requires a lot of starting cell materials like millions or tens of millions of cells. Many if not most interesting cellular models of development and disease are much rarer than that. Prominent examples include normal and cancer stem cells.

Q2: This spring you gave a great introductory talk at the Broad about epigenomics. Can you give a couple of visible examples of epigenetics in action?

Brad: The calico cat is a fun example. Calico cats are always female so they have two X-chromosomes. The different patches of fur color occur because there is a gene for coat color on the X, which is selectively inactivated in clonal patches of cells. The inactivation occurs by chemical modification of the DNA – there is no change in the DNA sequence – so it’s epigenetic. A less fun example is that epigenetic events also contribute to many types of cancer.

Q3: Why did you decide to study epigenomics?

Brad: I liked that it was uncharted territory. It was also clear early on that the tools of genomics had the potential to transform a field. So it was a good fit for me, and the Broad.

Q4: What’s your favorite thing about working at the Broad Institute and Harvard-affiliated hospitals?

Brad: I like working with interesting and capable people who think about big problems. There is also a lot of dedication to the mission, and people across the institution are pretty enthusiastic about moving science forward.

Q5: What are a couple of the big questions in science that you would like to see answered in the next ten years?

Brad: A big question in our field is the relationship between environment and the epigenome. We know that environmental cues can be remembered for a long-time – for example, in utero starvation can have long-term health consequences. We also know from model organism studies that certain chromatin structures are inherited when cells divide. There is some reason to think these two observations are related. But it’s really not clear at this point. My hope is that new tools for more precise and comprehensive analysis of the epigenome can begin to address this question and eventually help us understand how environment or perhaps even stochastic changes in chromatin contribute to human disease.