3D genome structure influences cancer

3D genome structure influences cancer

For the first time, scientists have examined how the three-dimensional (3D) structure of a patient’s genome can contribute to bladder cancer and pediatric brain tumors, according to a pair of Northwestern Medicine studies published in Science Advances and Genome Biology.

Within each cell, two-meter-long DNA needs to be properly folded and organized so that it can fit inside the nucleus, which is usually only a few micrometers in diameter. On many occasions, DNA forms “loops” that bring together genomic elements that are usually very far apart when the entire genome is unfurled. Some of these loops can lead to deleterious oncogene activation, and these studies help identify new therapeutic opportunities, according to Feng Yue, Ph.D., the Duane and Susan Burnham Professor of Molecular Medicine, senior author of the Genome Biology study and co-senior author of the Science Advances study.

“The unique 3D structure of cancer genomes can help us investigate what to target, both for biomarkers and for therapy,” said Yue, who is also an associate professor of Biochemistry and Molecular Genetics, of Pathology and director of the Center for Cancer Genomics at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Chromatin Loops Influence Bladder Cancer

The 3D structure of chromatin influences the progression of bladder cancer, according to a study published in Genome Biology. There are two major subtypes of muscle-invasive bladder cancer: basal and luminal. Luminal cancer is less aggressive, while basal cancer invades nearby tissues and is associated with worse survival. The two subtypes of bladder cancer have unique gene expression profiles and epigenetic signatures that could be used as a biomarker according to Yue, who is also the director of the Center for Advanced Molecular Analysis at the Institute for Augmented Intelligence in Medicine.

“By measuring this signature, you can have an estimate of whether their disease outcome is likely to be better or worse,” Yue said.

In the study, Yue and his collaborators profiled and analyzed epigenomic features and chromatin loops in multiple patient samples of each subtype, defining a unique regulatory signature. These loops often bring the distant regulator to their target genes, and each subtype has specific loops that regulate critical oncogenes in that subtype, according to Yue.

“They need to be linked in 3D space and talk to each other,” Yue said.

From these findings, the scientists identified more than 7,000 epigenetic regulatory elements, establishing an epigenetic profile for each subtype. Furthermore, the scientists also identified a novel regulatory gene, named NPAS2, that was highly associated with the luminal subtype. Patients with high NPAS2 expression had better survival, and this regulator could be used as a biomarker to determine the course of treatment or even perhaps to try and modify disease progression, according to Yue.

“We might be able to manipulate NPAS2 and other key regulators so that we can induce cancer subtype switching, which will have a profound influence on cancer patients prognosis and treatment,” Yue said. “That’s what we’re working on now.”

Abnormal Loops Fuel Brain Cancer

Abnormal chromatin loops have been linked to diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain cancer, according to the authors of the study published in Science Advances. Juan Wang, a third-year student in the Driskill Graduate Program in Life Sciences (DGP), was lead author of the study.

Most of the time, chromatin is condensed within the nucleus of a cell. During cell division, chromatin is unpacked to facilitate DNA replication and gene expression. However, some of that three-dimensionality is maintained during the “unpacking” process.

In normal cells, there is a baseline amount of these interactions, or chromatin loops. But when examining DIPG cells, the investigators discovered many more looping events. Notably, they measured a change in the proportion of the DNA that was crumpled versus that which was open to being read. Essentially, they found DNA being taken out of “storage” unnecessarily, contributing to new genetic interactions that help cause cancer.

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Time-keeping brain protein influences memory

Upsetting the brain’s timekeeping can cause cognitive impairments, like when jetlag makes you feel foggy and forgetful. These impairments may stem from disrupting a protein that aligns the brain’s time-keeping mechanism to the correct time of day, according to new research in fruit flies published in JNeurosci.

The brain contains ‘clock’ neurons that mold circadian behaviors and link them to cues from the environment, like light and seasonal changes. In fruit flies, the clock releases the peptide Pigment-dispersing factor (PDF) to synchronize the activity of the clock neurons and drive time-based behaviors like mating and sleep. PDF may also underlie memory formation, explaining the cognitive dysfunction that occurs when the clock is desynchronized from the environment.

Flyer-Adams et al. tested how well fruit flies with a functioning core clock but lacking the PDF output signal could learn. Flies without PDF had severely impaired memory . However, memory regulation by PDF likely occurs without direct signaling to the main memory structure of flies.

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Ability to eliminate spent proteins influences brain aging and individual life span

Aging is the main risk factor for dementia and Parkinson’s disease. As age progresses, toxic protein aggregates pile up in the brain and impair neuronal function. But why does that happen? An international team of scientists coordinated by the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) (Jena, Germany) and the Scuola Normale Superiore (Pisa, Italy) found answers by studying the brain of the turquoise killifish (Nothobranchius furzeri) brains. They delineate a timeline of molecular events during aging that is triggered by the early reduction of proteasome activity and culminates in aggregates formation. Remarkably, fish that preserve proteasome levels during aging live longer.

Protein homeostasis refers to the processes involved in the synthesis, folding, trafficking, location, and degradation of the entire set of proteins in the cell—the proteome. This complex network regulation is essential for all living organisms and its disturbance contributes to age-related diseases and influence life span.

Neurodegenerative diseases such as Alzheimer’s, ALS, and Parkinson’s are devastating conditions characterized by deterioration of neurons (nervous system cells) and/or spinal cord. These diseases have common features: they usually strike in mid to late-life and are accompanied by an accumulation of protein aggregates inside neurons. As a consequence of the increased age of our population, the percentage of people affected by these diseases increases steadily. Therefore, finding treatments to limit the damage of neurodegeneration is a pressing medical and societal need, and it critically depends on the understanding of how and why protein aggregates form during brain aging.

An international team led by researchers from the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) in Jena, Germany and the Scuola Normale Superiore in Pisa, Italy, together with the Centre for Misfolding Diseases in Cambridge, UK and the National Hellenic Research Foundation in Athen, Greece, has now used state-of-the-art transcriptomic and proteomic methods to investigate the chain of molecular events that lead to loss of protein homeostasis during brain aging. The researchers used Nothobranchius furzeri (killifish) as a model of aging to study mechanisms triggering protein homeostasis dysfunction. This fish species is the shortest-lived vertebrate bred under laboratory conditions—they have a life span of only 3—12 months! Age-dependent processes are exacerbated in this species, making it easier to detect changes in the concentration of RNAs and proteins, as compared to other model organisms. Also, aging induces in this fish pathological changes that mimic those typical of human aging, making it a practical vertebrate system for studying age-related neurodegenerative disorders.

During aging, proteins and RNAs become uncorrelated

“In order to identify the molecular events in the aging process that are responsible for the loss of protein homeostasis during brain aging, we used mass spectrometry-based proteomics in combination with RNA sequencing and analyzed protein aggregates in the brains of killifish of different ages,” says Dr. Alessandro Ori. The researchers analyzed brains of killifish from three different age groups: young sexually mature fish (5 weeks after hatching, wph), adult fish without aging characteristics (12 wph) and old fish that already showed signs of neurodegeneration (39 wph).

Messenger RNAs are used by the ribosome in the cell to synthetize proteins, which are biologically active molecules. “Measuring RNAs levels is easier that measuring protein levels and scientists very often measure changes in RNA levels under the assumption that the abundance of the corresponding proteins will change in a similar direction. The first result of our study is that during aging almost half of the proteins are regulated in opposite direction with respect to their corresponding RNA. This was a real surprise!” said Prof. Alessandro Cellerino from the Scuola Normale Superiore in Pisa, Italy. The study has now been published in the journal Molecular Systems Biology.

Age-related loss of the stoichiometry of essential protein complexes

“When comparing the data for the different age groups, we found that almost half of the approximately 9000 proteins that we managed to quantify are affected by aging,” says Dr. Alessandro Ori, group leader at FLI. These age-related changes result in abnormal regulation of proteins (subunits) that compose macromolecular protein complexes, the types of machinery responsible for all cellular activities. Protein complexes are built by different proteins that need to be assembled in specific ratios. Our cells have mechanisms to guarantee the proper building of these complexes by regulating the precise (stoichiometric) number of specific subunits. This tightly regulated process, however, is impaired in aging.

As Dr. Ori further explains, “there is a progressive loss of stoichiometry of protein complexes during aging, mainly affecting the ribosomes, which is one of the most important protein complexes in the cell, responsible for producing all other proteins.” The researchers demonstrated that ribosomes do not get adequately formed in old brains and aggregate, potentially influencing vital functions in the cell. Aggregation of ribosomes is not exclusive to killifish but also happens in mice, suggesting it is a conserved feature of brain aging.

Decrease in proteasome activity as an early sign of brain aging

“Ribosome aggregation is something devastating for cell survival. We wanted to understand what is causing it. More than that, we tried to find an early event during aging that triggers aggregates formation”, explains Dr. Erika Kelmer Sacramento, one of the first authors of the study that focused on the proteasome. Proteasomes are complexes of protein molecules that digest and recycle old or defective proteins and are an essential part of the protein homeostasis network (“garbage chipper” of the cell). The authors were able to show that proteasome activity is reduced early and progressively during the course of adult life and causes loss of protein complexes stoichiometry. They induced a reduction of proteasome activity during early adult life of the killifish using a specific drug for just four days and observed a premature aging signature including disrupted ratios of several protein complexes.

Low proteasome activity—short life span?

“As aging is the result of a chain of interconnected progressive events, it has been difficult to identify its early drivers. Decrease of proteasome activity is an early sign of brain aging, but is it relevant for aging of the entire organism? To answer this question, we correlated individual variations in proteasome activity with individual variations in lifespan,” explains Prof. Cellerino. So the team also compared the gene expression data of more than 150 killifish with their lifespan. The analysis showed that the individuals’ lifespan could be predicted based on changes in the expression of genes encoding for proteasomal proteins: fish that showed a greater decrease in proteasome transcripts at the beginning of life lived considerably shorter than fish able to maintain or increase proteasome expression. This finding supports the hypothesis that the reduction of proteasome activity is an early driver of aging in vertebrates.

“The FLI has made large investments in developing the killifish as a biological model. Our results show that this investment was well placed. The killifish revealed novel molecular aspects of aging: we were able to show for the first time that the maintenance of proteasome activity is an important factor for the correct stoichiometry of protein complexes involved in key biological functions such as protein synthesis, degradation, and energy production and ultimately for lifespan determination. These comprehensive results on RNA and protein regulation represent also a public resource that can be mined by scientific community, as it was the case for the genomic, transcriptomic and epigenetic resources previously generated at the FLI,” says Prof. Cellerino summarizing the most important results.

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