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A New View of the 3D Genome

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Caption: 3D model of a chromatin “forest.” Each sphere represents a tree-shaped domain of about 10 nucleosomes, the basic structural unit of DNA packaging. Larger domains are green; smaller ones are red. Credit: Northwestern University, Evanston, IL

 

This lush panoply of color might stir up daydreams of getting away to explore a tropical rain forest. But what you see here is a new model that’s enabling researchers to explore something equally amazing: how a string of DNA that measures 6 feet long can be packed into the microscopic nucleus of a human cell. Fitting that much DNA in a nucleus is like fitting a thread the length of the Empire State building underneath your fingernail!

Scientists have known for a while that that the answer lies in how DNA is folded onto spool-like complexes called chromatin, but many details of the process still remain to be worked out. Recently, an NIH-funded team, led by Vadim Backman and Igal Szleifer, Northwestern University, Evanston, IL, developed this new model of chromatin folding by pairing sophisticated mathematical modeling and optical imaging.In a study published in the journal Science Advances [1], the team found that chromatin is folded into a variety of tree-like domains along a chromatin backbone, which they liken to an aggregation of trees growing from the forest floor. The colorful spheres you see above represent trees of varying sizes.

Earlier models of chromatin folding had suggested that DNA folds into regular and orderly fibers. In the new study, the Northwestern researchers used their own specially designed Partial Wave Spectroscopic microscope. This high-powered system, coupled with electron imaging, allowed them to peer deep inside living cells to “sense” real-time alterations in chromatin packing. What makes their new view on chromatin so interesting is it suggests our DNA is packaged in a way that’s much more disorderly and unpredictable than initially thought.

Chromatin Forest
Caption: Schematic shows the interplay between transcription and chromatin packing. Inactive high DNA density (blue) regions and active low DNA density (red). The horizontal chromatin backbone includes RNA polymerase (green), activating factors (yellow), and repressing factors (purple). Credit: Huang et al., Sci. Adv. 2020

As Backman notes, it is reasonable to assume that a forest would be filled with trees of varying sizes and shapes. But you couldn’t predict the exact location of each tree or its particular size and configuration. The same appears to be true of these tree-like structures within chromatin. Their precise location and size vary, seemingly unpredictably, from cell to cell.

This apparently random DNA packing structure might seem surprising given chromatin’s importance in influencing the expression and function of our genes. But the researchers think such variability likely has its advantages.

Here’s the idea: If all of our cells responded to stressful conditions (such as heat or a toxic exposure) in exactly the same way and that way happened to be suboptimal, the whole tissue or organ might fail. But if differences in chromatin structure lead each cell to respond somewhat differently to the same stimulus, then some cells might be more likely to survive or even thrive under the stress. It’s a built-in way for cells to hedge their bets.

These new findings offer a fundamentally new three-dimensional view of the human genome. They might also inspire innovative strategies to understand and fight cancer, as well as other diseases. And, while most of us probably won’t be venturing off into the rain forest anytime soon, this work does give us all something to think about next time we’re enjoying the great outdoors in our own neck of the woods. 

Reference:

[1] Physical and data structure of 3D genome. Huang K, Li Y, Shim AR, Virk RKA, Agrawal V, Eshein A, Nap RJ, Almassalha LM, Backman V, Szleifer I. Sci Adv. 2020 Jan 10;6(2):eaay4055.

Links:

Deoxyribonucleic Acid (DNA) (National Human Genome Research Institute/NIH)

4D Nucleome (Common Fund/NIH)

Vadim Backman (Northwestern University, Evanston, IL)

Igal Szleifer (Northwestern University, Evanston, IL)

NIH Support: National Cancer Institute


Building a 3D Map of the Genome

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3D Genome Map

Credit: Chen et al., 2018

Researchers have learned a lot in recent years about how six-plus feet of human DNA gets carefully packed into a tiny cell nucleus that measures less than .00024 of an inch. Under those cramped conditions, we’ve been learning more and more about how DNA twists, turns, and spatially orients its thousands of genes within the nucleus and what this positioning might mean for health and disease.

Thanks to a new technique developed by an NIH-funded research team, there is now an even more refined view [1]. The image above features the nucleus (blue) of a human leukemia cell. The diffuse orange-red clouds highlight chemically labeled DNA found in close proximity to the tiny nuclear speckles (green). You’ll need to look real carefully to see the nuclear speckles, but these structural landmarks in the nucleus have long been thought to serve as storage sites for important cellular machinery.


DNA Barcodes Make for Better Single-Cell Analysis

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Variations within neurons

Caption: Single-cell analysis helps to reveal subtle, but important, differences among human cells, including many types of brain cells.
Credit: Shutterstock, modified by Ryan M. Mulqueen

Imagine how long it would take to analyze the 37 trillion or so cells that make up the human body if you had to do it by hand, one by one! Still, single-cell analysis is crucial to gaining a comprehensive understanding of our biology. The cell is the unit of life for all organisms, and all cells are certainly not the same. Think about it: even though each cell contains the same DNA, some make up your skin while others build your bones; some of your cells might be super healthy while others could be headed down the road to cancer or Alzheimer’s disease.

So, it’s no surprise that many NIH-funded researchers are hard at work in the rapidly emerging field known as single-cell analysis. In fact, one team recently reported impressive progress in improving the speed and efficiency of a method to analyze certain epigenetic features of individual cells [1]. Epigenetics refers to a multitude of chemical and protein “marks” on a cell’s DNA—patterns that vary among cells and help to determine which genes are switched on or off. That plays a major role in defining cellular identity as a skin cell, liver cell, or pancreatic cancer cell.

The team’s rather simple but ingenious approach relies on attaching a unique combination of two DNA barcodes to each cell prior to analyzing epigenetic marks all across the genome, making it possible for researchers to pool hundreds of cells without losing track of each of them individually. Using this approach, the researchers could profile thousands of individual cells simultaneously for less than 50 cents per cell, a 50- to 100-fold drop in price. The new approach promises to yield important insights into the role of epigenetic factors in our health, from the way neurons in our brains function to whether or not a cancer responds to treatment.


Creative Minds: A New Way to Look at Cancer

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Bradley Bernstein

Bradley Bernstein

Inside our cells, strands of DNA wrap around spool-like histone proteins to form a DNA-histone complex called chromatin. Bradley Bernstein, a pathologist at Massachusetts General Hospital, Harvard University, and Broad Institute, has always been fascinated by this process. What interests him is the fact that an approximately 6-foot-long strand of DNA can be folded and packed into orderly chromatin structures inside a cell nucleus that’s just 0.0002 inch wide.

Bernstein’s fascination with DNA packaging led to the recent major discovery that, when chromatin misfolds in brain cells, it can activate a gene associated with the cancer glioma [1]. This suggested a new cancer-causing mechanism that does not require specific DNA mutations. Now, with a 2016 NIH Director’s Pioneer Award, Bernstein is taking a closer look at how misfolded and unstable chromatin can drive tumor formation, and what that means for treating cancer.


Creative Minds: Studying the Human Genome in 3D

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Jesse Dixon

Jesse Dixon

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.