Shining Light on the Dark Matter of Biology

It is tempting to think we understand cells. They are small. They have DNA. They consume nutrients and make proteins. They grow and divide. Simple, right?

Actually, no. Researchers may have a broad understanding about the biology and chemistry of cells, but there is much that they do not know. For example, while many of the functions that keep cells alive and ticking are conducted by proteins with clearly defined shapes, many other functions are governed by a structureless class of proteins known as intrinsically disordered regions.

The proteins we are most familiar with can be thought of as being analogous to a tool like a wrench. A wrench has a certain shape that makes it ideal for turning nuts and bolts, and it is always in that shape. Intrinsically disordered proteins are not like that at all. They are dynamic. They are floppy. They wiggle around in space and change their shape. And because these proteins do not have a consistent shape, they have been hard to study and characterize.

Shasha Chong, who has recently joined Caltech's faculty in the Division of Chemistry and Chemical Engineering after receiving her PhD in chemistry and chemical biology from Harvard University and conducting postdoctoral research at UC Berkeley, wants to understand these proteins. We sat down with her to talk about her work.

Describe your work for us.

I have been studying how gene expression is regulated. Gene expression is fundamental to all the processes happening in our cells. How your tissues work, how an organism survives, and how it reproduces—it's all reliant on gene expression.

The first step of gene expression is transcription, which is where the DNA is copied into RNA. Regulation of transcription is important for every healthy cell. And, of course, when transcription goes wrong, it can lead to diseases.

I'm particularly interested in mammals. And in mammalian cells, the regulation of transcription is extremely complicated. We are still pretty far away from understanding how transcription is regulated. One important reason is that much of the regulation is mediated by intrinsically disordered regions, which are proteins that do not have clear shapes. These proteins are so difficult to understand because they don't fold into well-defined protein structures and cannot be understood by conventional analytic methods.

My way of studying them is to visualize and track these protein molecules one at a time in live cells. To observe their behaviors in the native state, I label proteins expressed by the cells with fluorescent tags using CRISPR, the genome-editing method. Single-molecule imaging is uniquely powerful for understanding biomolecular transactions. This method can provide in-depth insights that no other method is capable of providing. Using high-resolution single-molecule imaging, I have discovered a new type of interaction between the intrinsically disordered regions in transcription regulatory proteins. Such interactions mean a molecule can bind to a variable number of partners depending on surrounding conditions. Such interactions play an essential role in transcription.

Long term, I will be developing new imaging methods and combining them with other approaches to achieve two primary goals. I want to understand the fundamental rules that govern the interaction behaviors of intrinsically disordered regions and I want to elucidate the detailed mechanisms by which disordered regions mediate gene transcription under normal and disease conditions.

Can you talk more about intrinsically disordered regions and why they are important?

Given the recent advances of structural biology, lots of proteins have gotten their atomic structures solved. And by knowing those structures, we can learn lots of useful information, like which partners the proteins interact with and how they interact. But the methods used for understanding these proteins only work for proteins with one stable structure. Intrinsically disordered regions, or intrinsically disordered proteins, are flexible in nature and do not have a stable structure. Therefore, they cannot be described by classical structural description methods such as X-ray crystallography and cryo-electron microscopy.

These disordered regions are extremely abundant in proteomes—the collection of proteins within a cell or organism. For example, they constitute nearly half of the human proteome. They are involved in virtually every cellular process and perform many critical functions. But the mechanisms underlying these functions are largely unknown.

What are the big-picture questions you want to solve?

A lot of these disordered regions are known to play important roles in DNA transcription, and misregulation in transcription is linked to many diseases. More importantly, mutations in transcription-related disordered regions are directly implicated in many human diseases. By understanding intrinsically disordered regions and how they regulate transcription, we may learn more about treating different types of cancer, neurodegenerative diseases, and diabetes.

You also study the dark proteome. What is the dark proteome?

The dark proteome is another name for these intrinsically disordered regions. They can be thought of as the dark matter of biology because they make up a large portion of our bodies' proteins and play many roles in our bodies, but we know very little about them.

What are you looking forward to most in joining Caltech?

Caltech has really impressed me by having so many successful faculty members who are friendly and approachable even though they are giants in their fields. I'm looking forward to working with extremely brilliant colleagues and very motivated students. Everybody here seems to be really excited about their science and their career. That's really convinced me that Caltech is the best place for me to be.

What do you like to do with your free time?

I enjoy spending my time with my family—for example, with my toddler boy. Even just sitting with him watching him play with his toy cars is very relaxing.