cell
A New View of the 3D Genome
Posted on by Dr. Francis Collins
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.
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
Cool Videos: Patching and Sealing the Cell Membrane
Posted on by Dr. Francis Collins
Bill Bement describes himself as a guy who “passionately, obsessively, and almost feverishly” loves to study cells. His excitement comes through in our final installment of the American Society for Cell Biology’s Celldance 2014. Bement, an NIH grantee at the University of Wisconsin, Madison, shares his scanning confocal microscope with us for this fascinating glimpse into the rapid response of cells to repair holes, tears, and other structural damage in their protective outer membranes.
For most people, this damage response runs on biochemical autopilot, sealing any membrane break within seconds to keep the cell viable and healthy. But some people inherit gene mutations that make sealing and patching difficult, particularly in cells that operate under repetitive mechanical stress. For example, some forms of muscular dystrophy stem specifically from an inherited inability to repair breaks in the cell membrane of skeletal muscle cells. In one type of disease that affects both skeletal and cardiac muscle, a gene mutation alters the shape of a protein called dysferlin, which normally binds annexin proteins that, as noted in the video, play a vital role in patching holes. In the presence of a glitch in dysferlin, the rapid chain of biochemical events needed to enable such repair breaks down.
There’s still an enormous amount to learn about cell membrane repair, so it will be interesting to see what Bement’s microscope and camera will show us next.
Links:
Bement Lab, University of Wisconsin-Madison
Celldance 2014, American Society for Cell Biology
NIH Support: National Institute of General Medical Sciences
The Beauty of Smooth Muscle
Posted on by Dr. Francis Collins
We humans have long wondered how, exactly, we develop from embryos into adults. This photo of an embryonic smooth muscle cell hints at the tremendous complexity of this fundamental biological mystery. And for those of you who might be wondering just what smooth muscles are, they’re the involuntary muscles found in places like the walls of our blood vessels, the digestive tract, the bladder, and the respiratory system.
This exquisite photo was produced using laser scanning confocal microscopy — a precise imaging method that includes the dimension of depth for scientific analysis. Here, green is used to label thin filaments of the protein actin, which is a key component of the cell’s cytoskeleton, and blue indicates another protein, called vinculin, which is enriched in locations involved in cell-cell adhesion.
Slowly but surely, using all the technology and tools available to us, we are unraveling the mysteries of biology — and turning our discoveries into health.
Why We’re So Excited About Stem Cells
Posted on by Dr. Francis Collins
Certainly – as you can see here – stem cells are spectacularly beautiful. But they also hold spectacular promise for medicine. That’s why I immediately expressed my enthusiasm for Monday’s Supreme Court ruling that effectively enables NIH to continue conducting and funding responsible, scientifically worthy stem cell research.
There are many kinds of stem cells. This is a picture of induced pluripotent stem cells – or, iPS cells. Investigators have recently begun using iPS cells to model several neurological diseases – including Parkinson’s. The cells here have been treated with growth factors that coax them into becoming the dopamine producing (dopaminergic) neurons lost in Parkinson’s. The colorized markers indicate the presence of three proteins found within dopaminergic neurons: (1) the enzyme needed to produce dopamine (tyrosine hydroxylase, in blue), (2) a structural protein specific to neurons (Type III beta-tubulin, in green), and (3) a gene regulatory protein needed in dopaminergic neurons (FOXA2, in red). The color-mixing in some cells indicates that all three proteins are present – confirming that these cells are on their way to becoming dopaminergic neurons.
Today’s image is more than just a pretty picture. It’s a window into the ways that disease affects the body – and possibly the ways we might counter those affects. The NIH/NINDS web site has more information about how iPS cells are being used to study Parkinson’s and other neurological disorders.
Science Becomes Art
Posted on by Dr. Francis Collins
Credit: Dylan T. Burnette, NICHD, NIH
This stunning picture of a human bone cancer cell won artistic accolades: 3rd place in the Nikon Small World Competition. DNA, the blueprint of life, is actually blue in this photo. The yellow squiggles are little powerhouses called mitochondria that generate ATP ‘fuel’ for the cell. The purple wisps are filaments of actin, which help the cell move, keep its shape, and traffic chemicals from one part of the cell to another.
Happy New Year everyone.
