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Nucleus of the cell mapped in 3D

"With SPRITE, we were able to see thousands of molecules -- DNAs and RNAs -- coming together at various 'hubs' around the nucleus in single cells," said grad student Sofia Quinodoz.

The nucleus of the cell is where the action happens, but it's not easy to analyze the behavior of a massive genome inside an area 50 times smaller than the width of a human hair.

Now, for the first time, researchers have mapped the cell nucleus in 3D, revealing the packaging and organization of a cell's DNA in unprecedented detail.

Inside each cell is the same massive chain of DNA. But most of the coding lies dormant. The combination of genetic sequences within in the chain that are turned off or on -- and expressed via RNA -- determines the role and functionality of each cell.

The power of the genome relies on its unique organization, its ability to packaged within such a small space while still being easily accessible, so that genes can be appropriately turned on and off.

As showcased by the new 3D maps, the genome that is the six feet of DNA is joined in the nucleus by nuclear bodies, the cellular machinery designed to survey and augment the reams of genetic coding.

These nuclear bodies are able to efficiently sort through the multitudes of nucleic acids thanks to the genome's unique 3D structures, which make some genes more accessible -- and easier to ramp up or down the expression of -- and others harder to mess with.

The new 3D maps -- published this week in the journal Cell -- have allowed scientists to understand how DNA occupies space within the nucleus, as well as the ways different chromosomal regions interact with the surrounding cellular machinery.

To build the maps, scientists used an analytical technique called SPRITE, or Split-Pool Recognition of Interactions by Tag Extension. SPRITE involves the tagging of different regions within the nucleus with molecular barcodes. All the molecules within a single complex receive the same barcode, while all of the different complexes receive unique barcodes.

Later, after the cell is allowed to function as it would, the complexes are broken open and scientists examine the molecular barcodes to see which complexes are interacting with each other and where.

The mapping efforts showed molecules associated with inactive genes tend to interact with a part of the nucleus called the nucleolus, which features proteins that represses DNA and keeps genes turned off. Conversely, molecules associated with active genes tend to interact with a nuclear body called the nuclear speckle, a piece of cellular machinery that produces molecules that help express genes, or convert codes into proteins.

"With SPRITE, we were able to see thousands of molecules -- DNAs and RNAs -- coming together at various 'hubs' around the nucleus in single cells," Sofia Quinodoz, a grad student at the California Institute of Technology, said in a news release.

Previously, many scientists thought each section of the nucleus and each chromosome were quarantined in their own area.

"But now we see that multiple genes on different chromosomes are clustering together around these bodies of cellular machinery," Quinodoz said. "We think these 'hubs' may help the cell keep DNA that are 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."
By Brooks Hays

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