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August 11, 2017
Digest
New Imaging Technique Overturns Longstanding Model of DNA Folding

How can 6½ feet of DNA be folded into the tiny nucleus of a cell? Researchers funded by NIH have developed a new imaging method that visualizes a very different DNA structure, featuring small folds of DNA in close proximity. The study reveals that the DNA-protein structure, known as chromatin, is a much more diverse and flexible chain than previously thought. This provides exciting new insights into how chromatin directs a nimbler interaction between different genes to regulate gene expression and provides a mechanism for chemical modifications of DNA to be maintained as cells divide. The results were featured in the July 28 issue of Science.

For decades, experiments suggested a hierarchical folding model in which DNA segments spooled around 11 nanometer-sized protein particles assembled into rigid fibers that folded into larger and larger loops to form chromosomes. However, that model was based on structures of chromatin in vitro after harsh chemical extraction of cellular components.

Now, researchers at the Salk Institute, La Jolla, Calif., funded by the NIH Common Fund, have developed an electron microscopy technique called ChromEMT that enables the 3-D structure and packing of DNA to be visualized inside the cell nucleus of intact cells.

Contrary to the longstanding textbook models, DNA forms flexible chromatin chains that have fluctuating diameters between 5 and 24 nanometers that collapse and pack together in a wide range of configurations and concentrations.

The newly observed and diverse array of structures provides for a more flexible human genome that can bend at varying lengths and rapidly collapse into chromosomes at cell division. It explains how variations in DNA sequences and interactions could result in different structures that exquisitely fine tune the activity and expression of genes.

“This is groundbreaking work that will change the genetics and biochemistry textbooks,” said Dr. Roderic Pettigrew, director of NIBIB, which administered the grant. “It’s an outstanding example of how constantly improving imaging techniques continue to show the true structure of everything from neuronal connections in the brain to the correct visualization of gene expression in the cell. It reveals how these complex biological structures are able to perform the myriad intricate and elaborate functions of the human body.”

Immune System May Mount an Attack in Parkinson’s Disease

A new study suggests that T cells, which help the body’s immune system recognize friend from foe, may play an important role in Parkinson’s disease (PD). The study, published in the journal Nature, was supported by NINDS.

PD is a neurodegenerative disorder in which dopamine-producing brain cells die off, resulting in tremors, muscle stiffness, loss of balance and slow movement. Additional symptoms may include emotional changes and disrupted sleep.

“This collaboration between neuroscientists and immunologists provides important new evidence for ways in which the immune system can play a role in PD, a link that can be used to further define this interaction,” said Dr. Beth-Anne Sieber, a program director at NINDS.

Immune system may wage a battle in brain disorders: T cell from a healthy person.
Immune system may wage a battle in brain disorders: T cell from a healthy person.

IMAGE: NIAID

A research team examined the role of T cells in PD. Members collected blood samples from 67 individuals with Parkinson’s disease and 36 healthy controls. Immune cells were extracted from the samples and mixed with portions of the alpha-synuclein protein, which accumulates in the brains of people with PD and can result in cell death.

They found that T cells from people with PD responded to the presence of alpha-synuclein to a much greater degree than those gathered from the control group.

In particular, two regions of alpha-synuclein evoked reactions from T cells: a section that often contains mutations linked with PD and a portion undergoing a chemical change that can lead to accumulation of the protein in the brain.

The researchers identified four genetic variations that were associated with T cell reactivity to alpha-synuclein. More than half of people with PD carried at least one of those variants, compared to 20 percent of controls.

“These findings expose a potential biomarker for PD that may someday help in diagnosing the disease or be used to evaluate how well treatments are working,” said one of the researchers.

According to the authors, the results suggest that PD may have characteristics of an autoimmune disease, in which the immune system incorrectly attacks the body’s own cells.

Researchers Unlock Regenerative Potential of Cells in Mouse Retina

Cells within an injured mouse eye can be coaxed into regenerating neurons and those new neurons appear to integrate themselves into the eye’s circuitry, new research shows. The findings potentially open the door to new treatments for eye trauma and retinal disease. The study appeared in the July 26 issue of Nature and was funded in part by NEI.

“The findings are significant because they suggest the feasibility of a novel approach for encouraging regeneration in the mammalian retina, the light sensitive tissue at the back of the eye that dies in many blinding diseases,” said Dr. Tom Greenwell, program director at NEI. “Importantly, the investigation also demonstrates that newly generated cells in the mouse retina not only look and behave like neurons, they also wire correctly to the existing neural circuitry at the back of the eye.”

The study looked to the zebrafish for clues about how to encourage regeneration in the mouse eye. When a zebrafish injures its eye, cells within the eye naturally regenerate, allowing the fish to maintain vision. Mammals lack this regenerative ability.

In studying zebrafish, the research team homed in on Müller glia, a type of retinal cell that supports the health and functioning of neighboring neurons and that also exhibits an innate regenerative ability. Sometimes referred to as the stem cells of the zebrafish eye, Müller glia are the cells from which all other types of retinal cells are regenerated in the fish.

“We’re showing for the first time that Müller glia in the adult mouse can give rise to new neurons after injury, and these neurons have the gene expression pattern, the morphology, the electrophysiology and the epigenetic program to look like interneurons instead of glia,” one of the researchers said.

The studied cells had formed functioning synapses—connections from one neuron to another—and responded to light in a way that’s typical of a type of interneuron. The cells had also integrated with retinal cells that convey signals to the brain.

The findings suggest that the regenerated cells were making synapses and integrating into both sides of the circuitry, presynaptically and postsynaptically. This approach could be useful for treatment of acute eye injuries and central retinal arterial occlusion—a stroke of the eye. The next step is to boost Müller glia numbers, researchers said.

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