The cartography of the nucleus

Creating 3-D maps of DNA within the innermost parts of a cell.

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Image: SPRITE

Settled somewhere down in every one of your cells is the thing that appears like a magic trick: Six feet of DNA is bundled into a modest space 50 times smaller than the width of a human hair. This DNA blueprint for your whole body is folded, twisted, and compacted to fit into the nucleus of each cell.

Now, Caltech scientists have shown that how cells organize the seemingly immense genome in a clever manner. Through this study, they expect to search and access important genes.

Understanding the delicate three-dimensional organization of the genome is crucial, particularly because alterations in DNA structure have been linked to certain diseases such as cancer and early aging. According to scientists, Mapping and pinpointing adjustments in atomic structure may help in discovering answers for these diseases.

Despite the fact that most of the cells in each human body contain indistinguishable genomes, different types of cells are able to have diverse functions because genes can be expressed at varying levels. For instance, when a stem cell is forming into a neuron, a flurry of activity occurs in the nucleus to dial all down levels of gene expression. These levels would be extraordinary, for instance, if the stem cell was transforming into a muscle cell or if the cell were settling on the choice to self-destruct.

The nucleus also holds nuclear bodies that contain a high concentration of cellular machinery all working to accomplish similar tasks, such as turning on specific sets of genes or modifying RNA molecules to produce proteins in the cell. This nuclear body should have the capacity to effectively seek through six feet of DNA—roughly 20,000 total genes, in mammals to unequivocally discover and control its objectives.

Scientists demonstrated a novel way called SPRITE to three-dimensionally delineate how DNA is organized within the space of the nucleus and how areas of chromosomes interface with each other and with nuclear bodies. Through this system, scientists can examine clusters (or “complexes”) of molecules within the nucleus to see which molecules are interacting with each other and where they are located.

A gif of 3D regions of of the nucleus visualized with SPRITE. A 3D model of the nucleus made with SPRITE: DNA regions in the "inactive hub" on chromosomes 15 (orange) and chromosome 18 (green) coming together around a large nuclear body in the nucleus (blue) called the nucleolus (red). Credit: Courtesy of the Guttman laboratory
A gif of 3D regions of of the nucleus visualized with SPRITE.
A 3D model of the nucleus made with SPRITE: DNA regions in the “inactive hub” on chromosomes 15 (orange) and chromosome 18 (green) coming together around a large nuclear body in the nucleus (blue) called the nucleolus (red).
Credit: Courtesy of the Guttman laboratory

Scientists used SPRITE to discover that genes across different chromosomes (large folded structures of DNA) cluster together around specific nuclear bodies. Specifically, inactive genes—those that are turned off—across different chromosomes cluster together around a particular nuclear body called the nucleolus, which contains repressive proteins on DNA that keep genes turned off. Conversely, active genes grouped about another kind of nuclear body called the nuclear speckle, contain molecules that help turn the genes on and make them into proteins.

Sofia Quinodoz, the study’s first author said, “With SPRITE, we were able to see thousands of molecules—DNAs and RNAs—coming together at various ‘hubs’ around the nucleus in single cells. Previously, researchers theorized that each chromosome is kind of on its own, occupying its own ‘territory’ in the nucleus. But now we see that multiple genes on different chromosomes are clustering together around these bodies of cellular machinery. We think these ‘hubs’ may help the cell keep DNA that is all turned on or turned off neatly organized in different parts of the nucleus to allow cellular machinery to easily access specific genes within the nucleus.”

A paper describing the research appears in the June 7 online issue of the journal Cell.

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