Reeling in the Past: Research Gives New Life to Old Model of DNA Looping

November 29, 2017 | by Katie Neith

breakthroughs - arthur riggs Arthur Riggs, Ph.D.
In science, many a theory, model and approach to a question has been set aside by investigators to pursue different angles or even different fields. Sometimes though, these ideas are quietly first published in a paper or presentation before they are put away. And every so often, as City of Hope’s Arthur Riggs, Ph.D., knows well, “forgotten” work can provide groundbreaking insight for new research years later.

In 1990, Riggs, who is now the Samuel Rahbar Chair in Diabetes & Drug Discovery, director of the Diabetes & Metabolism Research Institute at City of Hope and director emeritus of Beckman Research Institute of City of Hope, was doing research on X chromosome inactivation, epigenetics and DNA methylation when he outlined a model for a new organizational principle.

He proposed that a process he dubbed “DNA reeling” was necessary for DNA in our chromosomes to be correctly organized in three-dimensional (3-D) space in order to function properly. It was a model for what is now called DNA looping and was published in the journal, Philosophical Transactions of the Royal Society B.

In each cell of the human body, there are roughly 6.5 feet of tightly wrapped and folded DNA molecules packed into chromosomes. The way this genetic material — or genome — is bent and folded determines the action of genes and, therefore, how proteins are produced at the correct place and time.

Prior to Riggs’ methylation work, it was known that the genome forms loops as a mechanism for gene regulation to occur, but it was unclear how these loops formed. Riggs proposed that DNA is actively “reeled in” toward relatively fixed protein complexes instead of the protein complexes moving along the DNA.

“I always thought my model had to be right, and am proud of it. But I could not think of good experiments to prove or disprove it at the time,” said Riggs, who is known for his pioneering work in the field of epigenetics and for his role in the development of technology that led to the first synthetic human insulin for the treatment of diabetes.

A recent article in the journal Nature reports on new work confirming Riggs’ proposals in his now 27-year-old model, with the author, Elie Dolgan, crediting Riggs’ 1990 paper as the first to propose the DNA reeling/loop extrusion model.  

The Nature feature story highlights research over the past few years that has elucidated how the genome forms DNA loops and yet stays untangled. It outlines support for Riggs’ model — now called loop extrusion — through the use of detailed, high-resolution maps of the human genome used to garner better insight into the 3-D organization of DNA in chromosomes.

“I was told by my mentor at the Salk Institute, ‘Art, most people think it’s important the number of people who pay attention to your work in the first year or two after it’s published. That’s nonsense. The only citations that are important are the ones that you get 20 years later,’” said Riggs in a previous story about his career in epigenetics. “And he’s right, of course. The ones you get 20 years later, they show that you’ve really done something.”

And despite putting his DNA reeling work on hold to focus on other inquiries, Riggs says he followed progress on efforts to determine chromosome structure. In fact, he recently took up this line of work again himself.

“I had been watching the technology develop, so I was enthusiastically supportive when my postdoc, Xizhe Zhang, came back from a Cold Spring Harbor meeting and said he wanted to use the Hi-C method to look at chromosome structure and function,” said Riggs. “This led to me telling him about my earlier work and then to a collaboration in applying Bayesian network analysis to Hi-C data.”

Hi-C is a technique for analyzing interacting fragments of DNA to determine how close they are to each other. Riggs and Zhang, along with Andrei Rodin, Ph.D., the Dr. Susumu Ohno Chair in Theoretical Biology and associate professor in the Department of Diabetes Complications & Metabolism, and Sergio Branciamore, Ph.D., assistant research professor in the Department of Diabetes Complications & Metabolism, used mathematical Bayesian network modeling to take a closer look at intrachromosomal interactions captured by high-resolution Hi-C studies.

They outlined their findings in a paper, “Analysis of High Resolution 3D Intrachromosomal Interactions Aided by Bayesian Network Modeling,” that was published online ahead of print on Nov. 13, 2017, in the Proceedings of the National Academy of Sciences.

“Our PNAS paper data does support the reeling/extrusion model I published in 1990 but, obviously, we are not the first to provide experimental support for the model,” said Riggs. “However, the application of Andrei Rodin's Bayesian Network analysis to chromosome interaction data is novel.”

Now, researchers around the globe are working to figure out what drives the DNA looping mechanism. Ultimately, new knowledge about the relationship between DNA organization in 3-D space and genome activity will aid in understanding genomic processes, including enhancer function, that play roles in diseases like cancer and diabetes.

Studies on the mechanism of DNA looping and changes in loops during differentiation of stem cells to mature adult cells is currently under active investigation in the Riggs laboratory by Zhang, Branciamore and Joshua Tompkins, Ph.D., assistant research professor in the Department of Diabetes Complications & Metabolism.

According to Riggs, important questions remain such as: What is the mechanism that reels in DNA toward a reeling-motor complex? What proteins are part of the motor complex? Can we devise genomic engineering methods to make novel loops?

“It gives me goosebumps every time I think about all the remarkable research Dr. Riggs has pioneered,” said David Horne, Ph.D., vice provost and associate director of Beckman Research Institute at City of Hope and the Dr. & Mrs. Allen Y. Chao Chair in Developmental Cancer Therapeutics. “He is clearly always ahead of the times — absolutely incredible.”

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