He was named a MacArthur ‘genius’ fellow for research on gene regulation, but still has imposter syndrome

The youngest of this year’s class of MacArthur “genius grant” fellows, 35-year-old Jason Buenrostro was just a graduate student when he pioneered a technique that’s become a mainstay for

studying how cells regulate gene expression.

While doing his doctoral work at Stanford University, with geneticists William Greenleaf and Howard Chang, he developed the assay for transposase-accessible chromatin, or ATAC-seq, a highly

sensitive and accurate method for identifying regions of the genome that are open, or accessible, for initiating the production of proteins encoded by the DNA.

“The fundamental truth that humans are all different and a lot of the differences stem from our DNA sequences motivated my research,” said Buenrostro, now an associate professor of stem cell

and regenerative biology with his own laboratory at Harvard University.

ATAC-seq has become the standard tool for research on the accessibility of chromatin (the packaging that wraps DNA into compact structures), as it is easier to use and less expensive than

other methods. Buenrostro and his colleagues have used single-cell ATAC-seq to track changes in chromatin accessibility across the trajectory of human blood cell formation and to identify

specific transcription factors that regulate blood cell development and may contribute to disease.

Buenrostro’s invention garnered him one of the 20 MacArthur grants this year, an accolade that comes with an $800,000 prize.

STAT spoke with Buenrostro — a first-generation American whose parents immigrated from Mexico — about the challenges he faced trying to get a start in biological research, the applications

of ATAC-Seq, and the technologies he hopes to work on in the future. This interview has been edited for length and clarity.

Tell us about what inspired your venture into molecular and cellular biology.

From a young age, I was captivated by the ongoing discoveries in the medical field. I was thinking about going into medicine, as a physician, but later realized that I wanted to understand

bioengineering and how cells work. I became more interested in the biochemical interactions of drugs and knew I wanted to pursue a career in researching biological pathways of cells.

However, growing up as a Latinx first-generation college student, there were not many examples or clear directives of how to go into academic research. Every step of the way I would grapple

with a new challenge, whether it was how to write a research statement for graduate school or once I got there, deciding what area of science I wanted to focus on in the umbrella of

genetics.

I think the biggest thing is when I moved forward with my journey, I faced imposter syndrome. It even happens now — I’ll walk into a room and be like, do I really deserve to be here?

Especially when I am in a room with people who don’t look like me. But I realized over time, a lot of people — including faculty and staff at Harvard — feel the same way. Given that we are

all from different backgrounds, it is normal to face imposter syndrome.

You and your colleagues pioneered this tool called ATAC-seq. How does this technology help us better understand cellular processes?

As a graduate student at Stanford University, I was very interested in understanding the genetic differences not only between individuals but also between cells. Much of our understanding of

how the human genome is working was not done in human samples but in organisms like yeast, cancer cell lines, etc. My colleagues and I really wanted to develop a tool that was going to take

various tissues of the human body, isolate individual packs of cells, and understand them.

One good marker of what our genome is doing is how opened or closed it is. For DNA that is more open in our bodies, it is being actively used by our cells. If it is closed or put away, it

becomes inactive. Understanding these markers led us to develop a tool called ATAC-seq, which measures open and closed regions of the genome. It identifies where chromatin has made a section

of DNA accessible for transcription, the process by which DNA information is copied to messenger RNA and transported to the cell’s protein-making machinery.

Over the years, we have used it to look at different cell types within the human body and it also enabled a new category of methods we have been championing called single-celled methods.

We later created SHARE-seq, which allows us to identify accessible DNA and gene expression in the same single cell. Using SHARE-seq and other innovative methods, we can understand that

certain areas of accessible chromatin correlate to genes that determine a cell’s lineage, or what type of specialized tissue or organ a cell will become. We can learn more about the

different communities of cells within tissues and understand how they work.

What are the applications of ATAC-seq in biomedicine and drug discovery?

Honestly, it has gotten beyond biomedicine and drugs. Every organism on the planet has a genome, and almost all organisms organize it into a structure called chromatin. ATAC-seq is good at

measuring open and closed versions of chromatin. It has been used to study plants, evolution, and health conditions. It is especially useful for understanding what parts of our genome are

active and therefore what are the genetic mutations or variants in those regions that make us different from each other.

It has been useful from a diagnostic perspective, but also provides insight in our ability to change, to intervene with treatments, in therapeutics as well. An example of how we use it can

be looked at with cancer. If we want to make a cancer cell grow less, we may want to first know why it’s growing so much, and how it’s interpreting its genome, and how it’s using its DNA

sequence to turn on genes that cause it to grow. ATAC-seq can be used to identify what genes are on and what genes are off in the cell. And by understanding why these genes may be on, we can

think about how to intervene.

We’ve seen that ATAC-seq can be so useful in understanding the mechanisms of cancer growth, as well as mechanisms of how the immune system kills cancer cells.

Tell us about recent work with developing DNA sequencing methods to better understand how spatial context impacts cellular function. What are the applications of this research?

Over the last few years, in addition to single-cell analyses, we have conducted spatial analyses where we see that this cell is next to that cell, and that cell is next to that cell. Keeping

cells in their original locations within tissues allows us to investigate how different cell types impact and are impacted by surrounding cells. Slide-DNA-seq is a tool we created that

identifies the spatial location of genetic mutations by mapping the organization of tissues.

We are currently building tools to understand how the interaction of cells are working. [One of] the applications of that has been to understand how tumors are growing and how the immune

system is fighting these tumors. It helps us understand the unique evolutionary pathways of cancer cells and of potential treatments.

I am thrilled about how this field continues to grow and innovate. By studying epigenomics, we can record what we know in the past to help predict the future. I never imagined what ATAC-seq

would be today when we created it many years ago. As we generate more and more data from sequencing DNA from hundreds of thousands of cells with every project, we gain a better understanding

of how our genome works every step of the way. Ultimately, I think this can provide unique opportunities to develop therapies for diseases and help save lives.