Human Genome's Spirals, Loops and Globules Come into 4-D View

A quest to unravel the architecture of the double helix is revealing the subtle genetic orchestration of life

The genome packs into the nucleus in a manner consistent with the structure of a fractal globule, shown herea polymer state that is extraordinarily dense, but entirely unknotted. Credit: Olena Shmahalo/Quanta Magazine. Globule courtesy Miriam Huntley, Rob Scharein, and Erez Lieberman Aiden

FromQuanta Magazine(findoriginal story here).

The nuclei from a half-million human cells could all fit inside a single poppy seed. Yet within each and every nucleus resides genomic machinery that is incredibly vast, at least from a molecular point of view. It has billions of parts, many used to activate and silence genesan arrangementthat allows individual cells to specialize as brain cells, heart cells and some 200 other different cell types. Whats more, each cells genome is atwitter with millions of mobile pieces that swarm throughout the nucleus and latch on here and there to tweak the genetic program. Every so often, the genomic machinereplicates itself.

At the heart of the human genomes Lilliputian machinery is the two meters worth of DNA that it takes to embody a persons 3 billion genetic letters, or nucleotides. Stretch out all of the genomes in all of your bodys trillions of cells, saysTom Misteli, the head of the cell biology of genomes group at the National Cancer Institute in Bethesda, Md., and it would make 50 round trips to the sun. Since 1953, when James Watson and Francis Crick revealed the structure of DNA, researchers have made spectacular progress in spelling out these genetic letters. But this information-storage view reveals almost nothing about what makes specific genes turn on or off at different times, in different tissue types, at different moments in a persons day or life.

To figure out these processes, we must understand how those genetic letters collectively spiral about, coil, pinch off into loops, aggregate into domains and globules, and otherwise assume a nucleus-wide architecture. The beauty of DNA made people forget about the genomes larger-scale structure, saidJob Dekker, a molecular biologist at the University of Massachusetts Medical School in Worcester who has built some of the most consequential tools for unveiling genomic geometry. Now we are going back to studying the structure of the genome because we realize that the three-dimensional architecture of DNA will tell us how cells actually use the information. Everything in the genome only makes sense in 3-D.

Genome archaeologists like Dekker have invented and deployed molecular excavation techniques for uncovering the genomes architecture with the hope of finally discerning how all of that structure helps to orchestrate life on Earth. For the past decade or so, they have been exposing a nested hierarchy of structural motifs in genomes that are every bit as elemental to the identity and activity of each cell as the double helix.

A better genetic microscope A close investigation of the genomic machine has been a long time in coming. The early British microscopist Robert Hooke coined the wordcellas a result of his mid-17th-century observations of a thin section of cork. The small compartments he saw reminded him of monks living quarterstheir cells. By 1710, Antonie van Leeuwenhoek had spied tiny compartments within cells, though it was Robert Brown, of Brownian motion fame, who coined the wordnucleusto describe these compartments in the early 1830s. A half-century later, in 1888, the German anatomist Heinrich Wilhelm Gottfried von Waldeyer-Hartz peered through his microscope and decided to use the wordchromosomemeaning color bodyfor the tiny, dye-absorbing threads that he and others could see inside nuclei with the best microscopes of their day.

During the 20th century, biologists found that the DNA in chromosomes, rather than their protein components, is the molecular incarnation of genetic information. The sum total of the DNA contained in the 23 pairs of chromosomes is the genome. But how these chromosomes fit together largely remained a mystery.

Then in the early 1990s, Katherine Cullen and a team at Vanderbilt University developed a method to artificially fuse pieces of DNA that are nearby in the nucleusa seminal feat that made it possible to analyze the ultrafolded structure of DNA merely by reading the DNA sequence. This approach has been improved over the years. One of its latest iterations, calledHi-C, makes it possible to map the folding of entire genomes.

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Human Genome's Spirals, Loops and Globules Come into 4-D View