New faculty Yarui Diao sheds light on DNA non-coding “Dark Matter”

From Regeneration Next Director, Ken Poss, Ph.D.:
On behalf of the Regeneration Next Initiative, I’m excited to welcome Yarui Diao, Ph.D., to Duke University. This month, Yarui joins us as a new Assistant Professor in the Department of Cell Biology. Yarui will also be an affiliate of Regeneration Next and hold an appointment in Orthopaedic Surgery. Regeneration Next partnered with Dean Klotman to recruit Yarui to Duke as part of an open search this past year conducted with the departments of Cell Biology and Biomedical Engineering.

Yarui followed a highly productive training in skeletal muscle regenerative biology with postdoctoral work in Bing Ren’s lab at UCSD, where he applied cutting edge gene-editing techniques to dissect genome regulatory elements at high throughput in stem cells. Here, he intends to explore the gene regulatory mechanisms that control skeletal muscle stem cell activity and is excited to form new collaborations – indeed, his work in both biology and technology spaces should be of interest to many faculty at Duke.

Regeneration Next Executive Director Sharlini Sankaran, Ph.D. spoke with Diao about his research and future plans.

Yarui Diao, Ph.D.

SS: Your research focuses on gene regulatory elements. What are they and why are they important?
YD: As the name suggests, “gene regulatory elements” refer to the non-coding DNA regions which control gene expression. When the human genome was first sequenced in 2003, scientists were surprised to find that only 2% of the human genome was made up of so-called “coding” genes. More than 98% of the sequence was non-coding. In fact, about 15 years ago these non-coding gene sequences used to be called “Junk DNA” or “Dark Matter”, and many people used to think they were non-functional.

But then came the rapid development of the field of epigenetics and next-generation sequencing technologies. These tools allowed us to learn that these non-coding regions of the genome contain extremely critical information to help the cells in our body learn when, where, and how much to turn on or off the gene expression program. These “non-coding” regulatory regions of the genome show highly cell type-specific activity. This activity is what directs cell differentiation – it is what makes our brain cells become brain cells, a muscle cell become a muscle cell, and so on. Each cell type has different morphology, different function, and different gene expression program.  You can think of gene regulatory elements as the “Menu” and “instructions” that tell the cell how develop and how to function.

SS: These elements are very important in cell development and differentiation, but they also play an important role in tissue regeneration. Can you tell us how gene regulatory elements are important in regenerative medicine?
YD: Gene regulatory elements play an important role in almost all biological processes, including tissue regeneration. Let’s take stem cells as an example. In different tissues, there are tissue-specific stem cells, and there are lineage-specific transcription factors that are tightly controlled by gene regulatory elements. These transcription factors need to recognize specific regulatory elements to “turn on” their activity. If we can get a better understand of how gene regulatory elements work, we can get a better understanding of stem cell fate, or how stem cells differentiate into different cell types.

If you get a better understanding of gene regulatory elements, it can help you understand the disease mechanisms that are involved in many degenerative disorders and also in the aging process.  We know that in aging, a lot of tissue types fail to regenerate at the same rate as in younger people, and these have to do with changes in gene regulation.

SS: How did you become interested in this area of research? Tell me a little bit more about your research.
YD: I spent my entire postdoctoral career studying gene regulation, but my interest in tissue regeneration dates back to my PhD studies. I wanted to understand how transcription factors can control stem cell fate (what types of cells the stem cells mature into). I found that the transcription factors need to bind to specific gene regulatory elements to do the job.  At that time, just 5 – 6 years ago, despite the crucial function of these regulatory elements, it was difficult to precisely identify them in the genome because there were no good tools to characterize the 98% of the DNA that consist of these non-regulatory elements.

So for my postdoctoral training, I took a departure from my PhD research of studying muscle stem cells to join Dr. Bing Ren’s lab to study gene regulation. Dr. Ren is well known for using cutting edge technology and tools for studying functions of the non-coding genome. Luckily, at that time, in 2013, there was a new technology called CRISPR-Cas9 that was being developed. This new technology gave me the ability to develop a new method and lead a project to study the functionality of these non-coding gene regulatory elements in a high throughput manner.

In my Ph.D. research I, used muscle stem cells as a model system for studying the gene regulation mechanism centered on a master transcription factor called Pax7. We know that Pax7 regulates muscle development and regeneration. Mice lacking Pax7 show severe defects in muscle stem cell activity and muscle regeneration and growth. Very interestingly, I found that loss of Pax7 causes cells to transition into adipocytes (Fat cells) instead of muscle cells.

Muscle stem cells are isolated (top) and undergo proliferation, differentiation, and fusion to form muscle fibers (bottom row, left to right). The entire process is tightly controlled by gene regulatory elements, whose dysregulation leads to muscular disorders in disease and aging. Image courtesy Yarui Diao.

SS: To clarify – muscle stem cells turned into fat cells? There may be a whole weight-loss industry that would be very interested in this!
YD: Yes. We showed that Pax7 binds to a few non-coding regulatory elements to suppress the fat cells’ fate. Without the Pax7, muscle stem cells that would have become muscle cells, matured into fat cells instead.

SS: What are the future implications of your research for human health and regenerative medicine?
YD: I plan to use muscle stem cells as a model system to understand how gene regulatory networks control muscle stem cell activity. Muscle stem cells are not as “exciting” or popular to study compared to, for example, brain or heart stem cells. The significance of muscle stem cells and their remarkable regenerative potency is often overlooked. We know it’s very hard for the brain to regenerate. It’s very hard for the heart to regenerate. But tissues like muscle and skin have remarkable regenerative ability and we should study them more.

If we look at diseases related to muscular degenerative disorders, I would say there is a very urgent need to understand the mechanisms that control muscle regeneration. For example, there are a lot of patients suffering from disorders like muscular dystrophy and muscular atrophy. Remember, muscles are not just there to support our limb movements. Muscles also control essential functions like moving the ribcage when we breathe – so if you have a defect in your muscle function, it can cause huge life-threatening problems.

There’s another type of condition called cachexia which occurs in patients with some chronic diseases like cancer. Cachexia is a muscle-wasting condition that causes a rapid loss of muscle function. The genetic and epigenetic basis of cachexia was overlooked by both scientists and physicians for many years, because it is not a direct cause of many diseases. But loss of muscle mass and function causes big trouble for patients. Cachexia is one of the provocative questions we need to address in cancer treatment. If we could find a way to manipulate muscle stem cell function, that would be very helpful to restore mobility and strength to these patients.

Also, aging is a condition that affects everyone eventually. Scientists know that in aged mice and aging people, muscle stem cells cannot be properly activated to generate new muscle cells. When injury occurs in older people, these muscle stem cells are less likely to be activated to heal the injury by new tissue formation. So, all these clinical needs are currently unmet mainly due to our limited understanding of the gene regulation mechanisms that control muscle stem cell activity.

SS: What are you looking forward to as you move to Duke?
YD: I’m very excited to establish my own research lab, as anyone would be after years of PhD and postdoctoral training! As I mentioned, I studied muscle stem cells in my PhD, and I studied gene regulatory elements in my postdoc, and I’ve had a long-standing interest in regenerative capacity and disease conditions. When I published my Cell Stem Cell paper during my PhD, I got a lot of phone calls from patients. Even though my research was very far removed from clinical treatments, there was still a lot of interest from patients. This encourages me as a scientist to do a better job of learning how translate this knowledge into future therapies to help people.

At Duke, and in North Carolina in general, there’s a very good environment to collaborate and push forward my research. There are a lot of people working to understand the role of gene regulatory elements in general, and also specifically in muscle stem cell function. For example Charlie Gersbach is a genome engineering expert who is also very interested in muscular disorders, and Ken Poss is a pioneer in heart regeneration who has uncovered tissue regeneration enhancer elements that help zebrafish hearts regenerate. I really look forward to working with these great people, trying to generate new knowledge and make an impact in science.

I’m also very excited to become a teacher. My parents are teachers in China, and my parents-in-law, my grandmother and grandfather, were all teachers. When I was a kid, I thought being a teacher is the best job in the world. I’m so happy to come to Duke to be a researcher in a great environment, but also to become a teacher to help train a new generation of future scientists.

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