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DNA

Mood-Altering Messenger Goes Nuclear

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Serotonin

Serotonin is best known for its role as a chemical messenger in the brain, helping to regulate mood, appetite, sleep, and many other functions. It exerts these influences by binding to its receptor on the surface of neural cells. But startling new work suggests the impact of serotonin does not end there: the molecule also can enter a cell’s nucleus and directly switch on genes.

While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.

To understand how serotonin contributes to switching genes on and off, a lesson on epigenetics is helpful. Keep in mind that the DNA instruction book of all cells is essentially the same, yet the chapters of the book are read in very different ways by cells in different parts of the body. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes in a particular cell without changing the underlying DNA sequence, switching them on and off or acting as “volume knobs” to turn the activity of particular genes up or down.

The marks include various chemical groups—including acetyl, phosphate, or methyl—which are added at precise locations to those spool-like proteins called histones. The addition of such groups alters the accessibility of the DNA for copying into messenger RNA and producing needed proteins.

In the study reported in Nature, researchers led by Ian Maze and postdoctoral researcher Lorna Farrelly, Icahn School of Medicine at Mount Sinai, New York, followed a hunch that serotonin molecules might also get added to histones [1]. There had been hints that it might be possible. For instance, earlier evidence suggested that inside cells, serotonin could enter the nucleus. There also was evidence that serotonin could attach to proteins outside the nucleus in a process called serotonylation.

These data begged the question: Is serotonylation important in the brain and/or other living tissues that produce serotonin in vivo? After a lot of hard work, the answer now appears to be yes.

These NIH-supported researchers found that serotonylation does indeed occur in the cell nucleus. They also identified a particular enzyme that directly attaches serotonin molecules to histone proteins. With serotonin attached, DNA loosens on its spool, allowing for increased gene expression.

The team found that histone serotonylation takes place in serotonin-producing human neurons derived from induced pluripotent stem cells (iPSCs). They also observed this process occurring in the brains of developing mice.

In fact, the researchers found evidence of those serotonin marks in many parts of the body. They are especially prevalent in the brain and gut, where serotonin also is produced in significant amounts. Those marks consistently correlate with areas of active gene expression.

The serotonin mark often occurs on histones in combination with a second methyl mark. The researchers suggest that this double marking of histones might help to further reinforce an active state of gene expression.

This work demonstrates that serotonin can directly influence gene expression in a manner that’s wholly separate from its previously known role in transmitting chemical messages from one neuron to the next. And, there are likely other surprises in store.

The newly discovered role of serotonin in modifying gene expression may contribute significantly to our understanding of mood disorders and other psychiatric conditions with known links to serotonin signals, suggesting potentially new targets for therapeutic intervention. But for now, this fundamental discovery raises many more intriguing questions than it answers.

Science is full of surprises, and this paper is definitely one of them. Will this kind of histone marking occur with other chemical messengers, such as dopamine and acetylcholine? This unexpected discovery now allows us to track serotonin and perhaps some of the brain’s other chemical messengers to see what they might be doing in the cell nucleus and whether this information might one day help in treating the millions of Americans with mood and behavioral disorders.

Reference:

[1] Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Farrelly LA, Thompson RE, Zhao S, Lepack AE, Lyu Y, Bhanu NV, Zhang B, Loh YE, Ramakrishnan A, Vadodaria KC, Heard KJ, Erikson G, Nakadai T, Bastle RM, Lukasak BJ, Zebroski H 3rd, Alenina N, Bader M, Berton O, Roeder RG, Molina H, Gage FH, Shen L, Garcia BA, Li H, Muir TW, Maze I. Nature. 2019 Mar 13. [Epub ahead of print]

Links:

Any Mood Disorder (National Institute of Mental Health/NIH)

Drugs, Brains, and Behavior: The Science of Addiction (National Institute on Drug Abuse/NIH)

Epigenomics (National Human Genome Research Institute/NIH)

Maze Lab (Icahn School of Medicine at Mount Sinai, New York, NY)

NIH Support: National Institute on Drug Abuse; National Institute of Mental Health; National Institute of General Medical Sciences; National Cancer Institute


Zooming In on Meiosis

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Meiosis

Credit: Simone Köhler, Michal Wojcik, Ke Xu, and Abby Dernburg, University of California, Berkeley

Meiosis—the formation of egg and sperm cells—is a highly choreographed process that creates genetic diversity in all plants and animals, including humans, to make each of us unique. This kaleidoscopic image shows cells from a worm exchanging DNA during meiosis.

You can see a protein-based polymer tether (green) from what’s called the synaptonemal complex. The complex holds together partner chromosomes (magenta) to facilitate DNA exchange in nuclei (white). Moving from left to right are views of the molecular assembly that progressively zoom in on the DNA, revealing in exquisite detail (far right) the two paired partner chromosomes perfectly aligned. This is not just the familiar DNA double helix. This is a double helix made up of two double helices!


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.


A Bacterium Reaches Out and Grabs Some New DNA

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Credit: Dalia Lab, Indiana University, Bloomington

If you like comic book heroes, you’ll love this action-packed video of a microbe with a superpower reminiscent of a miniature Spiderman. Here, for the first time ever, scientists have captured in real-time—and in very cool detail—the important mechanism of horizontal gene transfer in bacteria.

Specifically, you see Vibrio cholerae, the water-dwelling bacterium that causes cholera, stretching out a hair-like appendage called a pilus (green) to snag a free snippet of DNA (red). After grabbing the DNA, V. cholerae swiftly retracts the pilus, threading the DNA fragment through a pore on the cell surface for stitching into its genome.


Cryo-EM Images Capture Key Enzyme Tied to Cancer, Aging

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Each time your cells divide, telomeres—complexes of specialized DNA sequences, RNA, and protein that protect the tips of your chromosomes—shorten just a bit.  And, as the video shows, that shortening renders the genomic information on your chromosomes more vulnerable to changes that can drive cancer and other diseases of aging.

Consequently, over the last few decades, much research has focused on efforts to understand telomerase, a naturally occurring enzyme that helps to replace the bits of telomere lost during cell division. But there’s been a major hitch: until recently, scientists hadn’t been able to determine telomerase’s molecular structure in detail—a key step in figuring out exactly how the enzyme works. Now, thanks to better purification methods and an exciting technology called cryo-electron microscopy (cryo-EM), NIH-funded researchers and their colleagues have risen to the challenge to produce the most detailed view yet of human telomerase in its active form [1].

This structural biology advance is a critical step toward learning more about the role of telomerase in cancers, as well as genetic conditions linked to telomerase deficiencies. It’s also an important milestone in the quest for drugs targeting telomerase in different ways, perhaps to slow the growth of cancerous cells or to boost the proliferative capacity of life-giving adult stem cells.

One reason telomerase has been so difficult to study in humans is that the enzyme isn’t produced at detectable levels in the vast majority of our cells. To get around this problem, the team led by Eva Nogales and Kathleen Collins at the University of California, Berkeley, first coaxed human cells in the lab to produce larger quantities of active telomerase. They then used fluorescent microscopy, along with extensive knowledge of the enzyme’s biochemistry, to develop a multi-step purification process that yielded relatively homogenous samples of active telomerase.

The new study is also yet another remarkable example of how cryo-EM microscopy has opened up new realms of scientific possibility. That’s because, in comparison to other methods, cryo-EM enables researchers to solve complex macromolecular structures even when only tiny amounts of material are available. It can also produce detailed images of molecules, like telomerase, that are extremely flexible and hard to keep still while taking a picture of their structure.

As described in Nature, the researchers used cryo-EM to capture the structure of human telomerase in unprecedented detail. Their images reveal two lobes, held together by a flexible RNA tether. One of those lobes contains the highly specialized core enzyme. It uses an internal RNA template as a guide to make the repetitive, telomeric DNA that’s added at the tips of chromosomes. The second lobe, consisting of a complex of RNA and RNA-binding proteins, plays important roles in keeping the complex stable and properly in place.

This new, more-detailed view helps to explain how mutations in particular genes may lead to telomerase-related health conditions, including bone marrow failure, as well as certain forms of anemia and pulmonary fibrosis. For example, it reveals that a genetic defect known to cause bone marrow failure affects an essential protein in a spot that’s especially critical for telomerase’s proper conformation and function.

This advance will also be a big help for designing therapies that encourage telomerase activity. For example, it could help to boost the success of bone marrow transplants by rejuvenating adult stem cells. It might also be possible to reinforce the immune systems of people with HIV infections. While telomerase-targeted treatments surely won’t stop people from growing old, new insights into this important enzyme will help to understand aging better, including why some people appear to age faster than others.

As remarkable as these new images are, the researchers aren’t yet satisfied. They’ll continue to refine them down to the minutest structural details. They say they’d also like to use cryo-EM to understand better how the complex attaches to chromosomes to extend telomeres. Each new advance in the level of atomic detail will not only make for amazing new videos, it will help to advance understanding of human biology in health, aging, and disease.

References:

[1] Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nguyen THD, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, Collins K. Nature. 2018 April 25. [Epub ahead of publication]

Links:

High Resolution Electron Microscopy (National Cancer Institute/NIH)

Nogales Lab (University of California, Berkeley)

Collins Lab (University of California, Berkeley)

NIH Support: National Institute of General Medical Sciences   


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