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New Method Illuminates 3D Genome Structure of a Single Cell

human chromosomes
Tan's algorithm helps solve the "diploid problem" of identifying human chromosome pairs to determine 3D structure. | Jane Ades/ NIH Media Bank

Longzhi Tan has been named the 2019 Grand Prize winner of the Science & SciLifeLab Prize for Young Scientists for his work in developing an approach that allows us to visualize our genome's three-dimensional structure.

Dip-C, as the new method is called, can illuminate the structures of cellular components ranging from the whole nucleus to individual chromatin loops to alleles that differ in gene expression — a result that reveals the intimate relationship between 3D structure and diverse cellular function.

"Obtaining the sequence of the human genome was a landmark achievement, but we were left to unravel how human cells can have different functions by reading the genome differently," said Valda Vinson, deputy editor of Science. "It has become clear that the organization of the genome plays a key role, and [Tan] gives us a new view of how this happens."

Because the genes that organize the 3D genome are frequently disrupted in intellectual disabilities, autism, schizophrenia and many types of cancers, the insights Dip-C offers could improve scientists' understanding of both fundamental biology and human health.

The entirety of the human genome — nearly three billion base pairs of nucleotides helically wound and bundled into thread-like chromosomes — is packaged neatly within the nucleus of every human cell. Uncoiled and stretched end-to-end, it would span more than six feet in length.

While the human genetic code was cracked more than a decade ago, scientists have only recently begun to understand how these molecules fold to fit into a single cellular structure little more than 10 microns in diameter — the equivalent of packing 24 miles of fine thread into a tennis ball.

Through these pursuits, it's become increasingly clear that, beyond the sequence of the genome, the three-dimensional structures of the molecules themselves play a crucial role in regulating gene expression in individual cells.

Studying these three-dimensional structures in humans has been complicated. Previous sequencing methods similar to Tan's have been limited to haploid cells, which only contain a single set of chromosomes. However, the vast majority of human cells are diploid — they contain two complete sets of chromosomes, one from each parent and nearly indistinguishable from one another.

Longzhi Tan
Longzhi Tan

"Telling the two copies apart to resolve their 3D structures was previously thought to be an impossible task," said Tan.

To solve the "diploid problem," Tan, a postdoctoral research fellow at Stanford University, developed an algorithm based on the way chromosomes are separated in a cell. It accurately infers the common parent-of-origin of individual chromosomes.

"With our algorithm, we are able to create a beautiful 3D picture of all 46 chromosomes in each cell," said Tan.

In addition to visualizing chromosome structure in a cell, the approach allowed Tan to tell different cells apart without prior knowledge.

"Every cell has a different 3D genome structure. We found that, simply by knowing this structure, one can tell its cell type and, consequently, its biological functions," said Tan. The ability to "structure-type" single cells puts Dip-C on a growing list of single-cell tools useful for charting a comprehensive cell atlas.

In his grand-prize winning essay that appears in the Nov. 22 issue of Science, Tan puts his new method to the test by showing how it can illuminate previously unclear aspects of the structural basis for smell in mice.

Like humans, the mouse genome is diploid. In a mouse's nose, specialized neurons sense odors by expressing specialized olfactory receptors, which are a collection of roughly 1,100 receptor genes spanning 17 different chromosomes. Each neuron, however, is capable of expressing a single receptor while silencing all others. In this way, single neurons sense a specific subset of smells.

Using Dip-C, Tan and his colleagues mapped all olfactory receptor genes and their enhancers across mouse development and showed that chromosome organization changes during development and that the unique structure of olfactory receptor genes and their enhancers are the basis for mice's "one-neuron-one-receptor" approach to smell.

The SciLifeLab Prize, now in its seventh year, recognizes promising early-career scientists who conduct groundbreaking life-science research and includes a grand-prize award of $30,000. The categories for the 2019 prize were Cell and Molecular Biology; Genomics, Proteomics and Systems Biology; Ecology and Environment; and Molecular Medicine. The prize is organized by SciLifeLab (Science for Life Laboratory), a national center for advanced molecular life sciences in Sweden and the journal Science. The prize is also made possible through the generous support of the Knut and Alice Wallenberg Foundation — the largest private financier of research in Sweden — which primarily grants funding in natural sciences, technology and medicine.

"It is a great pleasure for SciLifeLab to co-host this young scientist prize again with Science and with the Knut and Alice Wallenberg Foundation. The four scientists selected as prize winners have made remarkable and groundbreaking discoveries in their fields. They have also shown great talent in condensing their work and thoughts into a short essay. These essays were successful in a highly competitive peer review process carried out by the editors of the Science magazine," said Olli Kallioniemi, director of SciLifeLab. "We congratulate the prize winners and look forward to welcoming them to Stockholm in December to deliver their prize lectures, take part in festive award ceremonies as well as engage in scientific discussions with the SciLifeLab community."

The 2019 award also recognizes three category winners whose essays will be published online in the journal Science. A podcast featuring additional commentary from Tan and the other winners will be available on Nov. 22.

2019 Grand Prize Winner:

Longzhi Tan: For his essay, " Three-Dimensional Genome Structure of a Single Cell ." Tan received his undergraduate degree in physics from the Massachusetts Institute of Technology and doctorate from Harvard University. Tan is a postdoctoral scholar at Stanford University and his research is focused on understanding 3D genome structure and its role in the diverse functions of individual human cell types.

2019 Category Winners:

Barbara Klump: For her essay on the topic of ecology and environment, " Tool-Using Crows, Culture and What It Means to Be Human." Klump received her Diplom-Biologin from Heidelberg University and her Ph.D. from the University of St. Andrews. Klump is a postdoctoral research fellow at the Max Planck Institute for Ornithology where she explores animal cognition and how a species' ecology and social structure shape its natural behaviors.

Humsa Venkatesh : For her essay on the topic of molecular medicine, " The Neural Regulation of Cancer." Venkatesh earned her undergraduate degree from the University of California, Berkeley and her Ph.D. from Stanford University. Venkatesh is a postdoctoral research fellow at Stanford where her research aims to reveal how cancers use the activity of neural networks to promote their growth.

Zibo Chen : For his essay on the topic of cell and molecular biology, " Creating the Protein Version of DNA Base Paring." Chen received his undergraduate degree from the National University of Singapore and Ph.D. from the University of Washington. Chen is a postdoctoral scholar at the California Institute of Technology focusing on building synthetic circuits using newly designed proteins.