Creative Minds: Studying the Human Genome in 3D

Posted on May 4th, 2017 by Dr. Francis Collins

As a kid, Jesse Dixon often listened to his parents at the dinner table discussing how to run experiments and their own research laboratories. His father Jack is an internationally renowned biochemist and the former vice president and chief scientific officer of the Howard Hughes Medical Institute. His mother Claudia Kent Dixon, now retired, did groundbreaking work in the study of lipid molecules that serve as the building blocks of cell membranes.

So, when Jesse Dixon set out to pursue a career, he followed in his parents’ footsteps and chose science. But Dixon, a researcher at the Salk Institute, La Jolla, CA, has charted a different research path by studying genomics, with a focus on understanding chromosomal structure. Dixon has now received a 2016 NIH Director’s Early Independence Award to study the three-dimensional organization of the genome, and how changes in its structure might contribute to diseases such as cancer or even to physical differences among people.

The human body is made up of trillions of cells, each much too small to see without a microscope. And yet, if you could unwind and stretch the DNA contained within the nucleus of any one of those vanishingly small cells, you’d find it’s more than 6 feet long!

How is that possible? It takes a lot of careful folding and packaging. It also requires that the genome is arranged to ensure that the right genes are activated in the right place and at the right time. That’s because DNA is not a disorganized mass of spaghetti in the nucleus. Instead, strands of DNA wrap around special spool-like histone proteins. This strand-and-spool complex, called chromatin, can also form larger looping structures as sections of DNA pinch together, bringing seemingly distant DNA sequences into close proximity, affecting the activity of genes that lie nearby. Those loops have potentially important implications for genome function in health and disease.

Dixon is hoping to learn more about how cells produce these 3D chromatin structures. He’ll watch as chromatin unravels and then reforms during cell division. He’ll also observe changes in chromatin structure as cells differentiate to form other cell types.

To understand more about how those looping structures are built, he’ll apply the latest CRISPR/Cas9 gene-editing tools. Dixon will introduce precise changes in the underlying DNA sequence, allowing him to explore their consequences for the chromatin structure and the cell. Ultimately, he hopes to identify the minimal requirements for creating a chromatin loop.

When Dixon visits with his parents these days, he has plenty of ideas to offer during mealtime conversations. So does his sister Sarah, a pediatrician at a community health center in San Diego. Must be a pretty interesting home to visit!

Links:

Dixon Lab (Salk Institute, La Jolla, CA)

Dixon NIH Project Information (NIH RePORTER)

NIH Director’s Early Independence Award (Common Fund)

NIH Support: Common Fund