Tag Archives: #genes

Biology

Gene Plays Major Role in Brain Development (Biology)

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Study by the University of Bonn shows that mutations of the investigated gene manifest in different patterns of inheritance

The so-called Plexin-A1 gene seems to play a more extensive role in brain development than previously assumed. This is shown by a current study led by the University Hospital Bonn and the Institute of Anatomy of the University of Bonn with more than 60 international partners. The gene is also interesting for another reason: Its mutations are inherited either dominantly or recessively, depending on which part of the gene is affected. The results of the study are now published in the journal “Genetics in Medicine”.

When the Augustinian monk Gregor Mendel crossed white-flowering with purple-flowering pea plants in the mid-19th century, he made an interesting discovery: The offspring were all purple. He therefore called this trait dominant, while the white blossom color was recessive. The reason for this phenomenon: In peas, each gene occurs twice. One version comes from the maternal plant and the other from the paternal plant. If a pea has inherited the gene for purple flower color from one parent, but the gene for white flower color from the other, purple wins. Only when two genes for white flowers come together in the offspring plant is it white.

Humans also have genes that are inherited either dominantly or recessively. However, the case is not so clear for the mutations investigated in the study: Some of them are dominant, meaning that a mutation inherited either by the mother or by the father is sufficient for the mutation to have an impact. Others, however, are recessive. “This has also been observed sporadically with other genes, but it was still unexpected,” explains Dr. Gabriel Dworschak, pediatrician at the University Children’s Hospital who conducted his research at the Institute of Anatomy and the Institute of Human Genetics.

Malformations of the brain and eyes

The gene came into the focus of the researchers when they examined a girl with severe malformations of the esophagus, brain and eyes at University Hospital Bonn. A genetic analysis revealed that her Plexin-A1 gene was different from that of healthy individuals. “We then searched a database for other affected individuals with mutations in the plexin gene,” explains Prof. Dr. Heiko Reutter, physician at the University Children’s Hospital and staff member at the Institute of Human Genetics at the University of Bonn.

The researchers have now found a total of ten patients in this way; they come from seven families. “The affected individuals all had different parts of the Plexin-A1 gene altered,” Dworschak points out. “Five of these mutations are inherited recessively; the remaining three are dominant.” Further analysis helped the researchers understand why this is the case: The Plexin-A1 gene contains the building instructions for a receptor. It is located in the membrane that surrounds the nerve cells like a thin skin. Certain messenger molecules can dock onto its outer surface. This then triggers a response at the other end of the receptor that protrudes into the cell.

“If a mutation affects the outside of the receptor, it can no longer receive signals,” speculates Dworschak. “However, if only one of the two Plexin-A1 versions is affected, there are enough intact receptors to compensate.” Mutations on the outside are therefore probably recessive. A defect on the inside of the receptor, however, can result in a serious misregulation of the cell. It may be enough for only one version of the Plexin-A1 gene to be altered in this way to cause significant damage. “We therefore think that such mutations are dominant, and we then speak of a dominant-negative effect,” says Dworschak.

Different symptoms

Overall, affected individuals show a wide range of symptoms. What they all have in common, however, is that their brain development is disrupted to varying degrees. Many of them also have malformations of the eyes and skin. “It was known that the Plexin-A1 gene is important in the growth of nerve cell extensions,” Reutter explains. “Nerve sprouting plays an essential role in the development of many organs. The observed malformations in affected individuals could therefore be caused by the disrupted development of certain nerve fibers.” A follow-up study at the Institute of Anatomy is currently investigating this question.

The Plexin-A1 gene performs an important function not only in us, as studies on a completely different species show. The researchers used the expertise of the working group led by Prof. Dr. Benjamin Odermatt from the Section of Neuroanatomy. The zebrafish serves as a model organism here – not only because it is easy to keep in terms of animal welfare requirements and can be bred quickly: Many of its genes are found in a similar form in humans. This includes the Plexin-A1 gene. “If we switch off this gene in zebrafish, brain development disorders similar to those in humans appear,” Dworschak explains. He hopes that the results of the study will help to better understand the complex processes involved in brain development.

Participating institutions and funding:

The study involved institutions from the USA, Turkey, India, Saudi Arabia, Pakistan, the United Kingdom, Australia, France, Canada, Italy and Germany. Dr. Jaya Punetha of Baylor College of Medicine in Texas is lead author of the study, together with Dr. Dworschak. The work was supported, among others, by the German Research Foundation (DFG) and by various funding agencies in the participating countries.

Featured image: Fluorescence image of two zebrafish embryos – After switching off the Plexin-A1 gene (bottom), malformations of the nervous system occur, such as a pathological enlargement of the neural fluid spaces in the brain (left).© (c) Dr. Gabriel Dworschak / University of Bonn

Publication: Gabriel C. Dworschak et al: Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies; Genetics in Medicine; DOI: 10.1038/s41436-021-01196-9

Provided by University of Bonn

Medicine

Genes Associated With COVID-19 Risk Identified (Medicine)

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Having genetic risk variants in the ABO gene might significantly increase the chances of developing COVID-19, and other genes may also increase COVID-19 risk, according to research presented at the ATS 2021 International Conference.

Much about COVID-19 remains a medical mystery, including whether certain genes place individuals at greater risk of contracting the SARS-CoV-2 virus, which causes COVID-19. Ana Hernandez Cordero, PhD, postdoctoral fellow with the Centre for Heart Lung Innovation, University of British Columbia, and colleagues used integrative genomics combined with proteomics to identify these genes.

Genomic research identifies specific genes that may play a role in biological processes such as the development of disease, while proteomics does the same for proteins. Researchers can get a fuller picture of disease processes by integrating tools to investigate both.

“DNA is a big, complex molecule and so, genetic associations alone cannot pinpoint the exact gene responsible for COVID-19,” said Dr. Hernandez. “However, by combining COVID-19 genetic information with gene expression and proteomic datasets, we can figure out which genes are driving the relationship with COVID-19.”

The researchers combined genetic information with an examination of lung gene expression to identify genetic variants that were controlling gene expression in the lung that were responsible for COVID-19. The researchers identified specific genes’ markers that share their effects on gene expression and protein levels with COVID-19 susceptibility. For the analysis, they used bioinformatics to integrate: (1) a genomic dataset obtained from patients who were infected with SARS-CoV-2 as well as non-infected individuals (controls); (2) lung and blood tissue gene expression datasets from clinical populations (non-COVID-19); and (3) a proteome dataset obtained from blood donors (non-COVID-19).

By doing this, they found that several genes responsible for the immune system’s response to COVID-19 are also involved in COVID-19 susceptibility. What they discovered was supported by the findings of previous research.

Looking for candidate genes in blood proteins, they were able to go one step further in connecting the effects of genes to susceptibility to COVID-19. Blood proteomics can also help identify markers in the blood that can be easily measured to indicate disease status, and potentially, to monitor the disease.

“By harnessing the power of genomic information, we identified genes that are related to COVID-19,” said Dr. Hernandez. “In particular, we found that the ABO gene is a significant risk factor for COVID-19. Of particular note was the relationship between the blood group ABO and COVID-19 risk. We showed that the relationship is not just an association but causal.”

In addition to the ABO gene, Dr. Hernandez and colleagues found that people carrying certain genetic variants for SLC6A20, ERMP1, FCER1G and CA11 have a significantly higher risk of contracting COVID-19. “These individuals should use extreme caution during the pandemic. These genes may also prove to be good markers for disease as well as potential drug targets.”

Several of the genes identified in the researchers’ analysis have already been linked with respiratory diseases. For example, ERMP1 has been linked to asthma. CA11 may also elevate COVID-19 risk for people with diabetes.

Genetic associations for COVID-19 and gene and protein expression were combined using integrative genomics (IG). IG aims to identify mechanisms (for example: gene expression levels) that connect the effects of the genetic code to a complex disease. These methods, although complex, are also fast and their outcomes can help researchers to prioritize candidate genes for in vitro (in the lab) and in vivo (in living organisms) testing.

Dr. Hernandez added, “Our research has progressed since the time that we first conducted this analysis. We have now identified even more interesting candidates for COVID-19 such as IL10RB, IFNAR2 and OAS1. These genes have been linked to severe COVID-19. Their role in the immune response to viral infections and mounting evidence suggest that these candidates and their role in COVID-19 should be further investigated.”

Reference: Hernandez Cordero, X. Li, S. Milne et al., “Integrative Genomic Analysis Highlights Potential Genetic Risk Factors for Covid-19”, ATS, 2021. VIEW ABSTRACT

Provided by ATS

Biology

New Snailfish Genome Reveals How They Adapted to the Pressures of Deep-sea Life (Biology)

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The genome contains extra genes for enzymes that help stabilize its proteins and DNA under high pressures

A new whole genome sequence for the Yap hadal snailfish provides insights into how the unusual fish survives in some of the deepest parts of the ocean. Xinhua Chen of the Fujian Agriculture and Forestry University and Qiong Shi of the BGI Academy of Marine Sciences published their analysis of the new genome May 13th in the journal PLOS Genetics.

Animals living in deep-sea environments face many challenges, including high pressures, low temperatures, little food and almost no light. Fish are the only animals with a backbone that live in the hadal zone–defined as depths below 6,000 meters–and hadal snailfishes live in at least five separate marine trenches. Chen, Shi and their colleagues constructed a high-quality whole genome sequence from the Yap hadal snailfish to understand how it has adapted to life in the deep sea. The fish was captured from the Yap Trench in the western Pacific Ocean at a depth of about 7,000 meters.

Analysis of the new genome revealed multiple adaptations for living in a cold, dark, high-pressure environment. The snailfish carries extra genes for DNA repair, which may help keep its genome intact under high pressures. It also has five copies of a gene for an enzyme that takes a compound produced by bacteria in its gut and transforms it into one that stabilizes the structure of proteins under high hydrostatic pressure. The snailfish has also lost certain genes involved in vision, taste and smell, which are likely unnecessary in its dark, food-limited environment.

These new findings offer clues into the mechanisms that snailfish have evolved to survive in oceanic trenches. However, the researchers point out that further studies will be needed to confirm the functions of these genetic changes. Additionally, the high-quality genome sequence can serve as a resource for future in-depth investigations of snailfish and other animals living in the hadal zone.

Chen adds, “Many genes associated with DNA repair show evidence of positive selection and have expanded copy numbers in the genome of Yap hadal snailfish, which potentially reflect the difficulty of maintaining DNA integrity under high hydrostatic pressure. The five copies of the trimethylamine N-oxide (TMAO)-generating enzyme flavin-containing monooxygenase-3 gene (fmo3) and the abundance of trimethylamine (TMA)-generating bacteria in the gut of Yap hadal snailfish could provide enough TMAO to improve protein stability under hadal conditions.”

Funding: This work was supported by grants from National Key R&D Program of China (2018YFD0900602; https://service.most.gov.cn) to Y.M., and National Program on the Key Basic Research Project (2015CB755903; https://service.most.gov.cn), China Agriculture Research System (CARS-47; http://www.cars.ren), China Ocean Mineral Resources R&D Association Program (DY135-B2-16; http://www.comra.org), and Special Fund for Marine Economic Development of Fujian Province (FJHJF-L-2019-2; https://hyyyj.fujian.gov.cn/) to X.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Featured image: Yap hadal snailfish (YHS) in situ at 6,903 m (above) and after capture (below). © Mu Y et al., 2021, PLOS Genetics

Reference: Mu Y, Bian C, Liu R, Wang Y, Shao G, Li J, et al. (2021) Whole genome sequencing of a snailfish from the Yap Trench (~7,000 m) clarifies the molecular mechanisms underlying adaptation to the deep sea. PLoS Genet 17(5): e1009530. https://doi.org/10.1371/journal.pgen.1009530

Provided by PLOS

Neuroscience

Stimulating Environments Boost the Brain; Now Scientists Have Found The Genes Responsible (Neuroscience)

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Results show major role of regulatory ‘epigenetic’ changes to genomic regions important for cognition and mental health in humans

Environmental enrichment — with infrastructure, unfamiliar odors and tastes, and toys and puzzles — is often used in zoos, laboratories, and farms to stimulate animals and increase their wellbeing. Stimulating environments are better for mental health and cognition because they boost the growth and function of neurons and their connections, the glia cells that support and feed neurons, and blood vessels within the brain. But what are the deeper molecular mechanisms that first set in motion these large changes in neurophysiology? That’s the subject of a recent study in Frontiers in Molecular Neuroscience.

Here, a multinational team of scientists used a large molecular toolbox to map, in unprecedented detail, how environmental enrichment leads to changes in the 3D organization of chromosomes in neurons and glia cells of the mouse brain, resulting in the activation or deactivation of a minority of genes within the genome. They show that genes which in humans are important for cognitive mental health are especially affected. This finding could inspire the search for novel therapies.

Enrichment first causes the 3D structure of chromosomes to ‘open up’

“Here we show for the first time, with large-scale data from many state-of-the-art methods, that young adolescent mice that grew up in an extra stimulating environment have highly specific ‘epigenetic’ changes — that is, molecular changes other than in DNA sequence — to the chromosomes within the cells of the brain cortex,” says corresponding author Dr Sergio Espeso-Gil from the Center for Genomic Regulation in Barcelona, Spain.

He continues: “These increase the local ‘openness’ and ‘loopiness’ of the chromosomes, especially around DNA stretches called enhancers and insulators, which then finetune more ‘downstream’ genes. This happens not only in neurons but also in the supportive glia cells, too often ignored in studies about learning.”

Espeso-Gil and colleagues raised laboratory mice for the first month after birth in social groups inside housing with Lego blocks, ladders, balls, and tunnels that were frequently changed and moved around. As a control, mice were raised in smaller groups inside standard housing. The authors then used a swathe of complementary tools to look for molecular changes in neurons and glia cells within the brain cortex. These included changes in the 3D structure of chromosomes, in particular the local ‘chromatin accessibility’ (openness) and ‘chromatin interactions’ (where distant genes are brought together through loops, to coordinate activity).

Epigenetic ‘master’ switches

They show that one ‘master’ switch operational after environmental enrichment is a locally increased activity of the protein CTCF, which stimulates chromatin interactions within and between chromosomes. A second master switch works by locally increasing chromatin accessibility, especially within the pyramidal neurons that are important for cognition. A third is the highly localized adding of CH3- (methyl) groups to the important chromosomal protein histone H3, a change which activates nearby genes.

These switches mainly occur around genomic regions that contain enhancers, regulatory DNA that (when bound to proteins called transcription factors) can activate neighboring genes. Also affected were genomic regions with insulators, regulatory DNA that can override the gene-activating effect of neighboring enhancers.

The authors conclude that growing up in an enriched environment causes highly local and specific epigenetic changes in neurons and glia cells. These then change the activity — predominantly by activation rather than inhibition — of a minority of genes within the genome. Overall, 0.2-0.4% of all enhancers and 2-5% of all promoters (i.e. start sites for the first step of gene expression, where DNA is transcribed into protein-coding or regulatory RNA) are affected.

Link to mental health in humans

“Our results show that many of the genes involved are known to play a role in the growth and differentiation of neurons, the development of blood vessels, the formation and patterning of new synaptic connections on neurons, and molecular pathways implicated in memory and learning in mice,” says Espeso-Gil.

“And when we look for parallel regions in the human genome, we find many regions that are statistically associated with differences in complex traits such as insomnia, schizophrenia, and Alzheimer’s in humans, which means that our study could inform future research on these disorders. This points to the potential of environmental enrichment in therapies for mental health. Our research could also help to guide future research on chromatin interactions and the poorly known importance of glial cells for cognitive mental health.”

Reference: Sergio Espeso-Gil, Aliaksei Z. Holik et al., “Environmental Enrichment Induces Epigenomic and Genome Organization Changes Relevant for Cognition”, Front. Mol. Neurosci., 05 May 2021 | https://doi.org/10.3389/fnmol.2021.664912

Provided by Frontiers

Medicine

U-M RNA Scientists Identify Many Genes Involved in Neuron Development (Medicine)

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Neurons result from a highly complex and unique series of cell divisions. For example, in fruit flies, the process starts with stem cells that divide into mother cells (progenitor cells), that then divide into precursor cells that eventually become neurons.

A team of the University of Michigan (U-M), spearheaded by Nigel Michki, a graduate student, and Assistant Professor Dawen Cai in the departments of Biophysics (LS&A) and Cell and Developmental Biology at the Medical School, identified many genes that are important in fruit flies’ neuron development, and that had never been described before in that context.

Since many genes are conserved across species such as between fruit flies (Drosophila), mice, and humans, what is learnt in flies can also serve as a model to better understand other species, including humans. “Now that we know which genes are involved in this form of neurogenesis in flies, we can look for them in other species and test for them. We work on a multitude of organisms at U-M and we’ve the potential to interrogate across organisms,” explains Michki. “In my opinion, the work we did is one of the many pieces that will inform other work that will inform disease,” adds Michki. “This is why we do foundational research like this one.”

Flies are also commonly used in many different types of research that might benefit from having a more comprehensive list of the fly genes with their associated roles in neuron cell development.

The discovery

Neurons are made from stem cells that massively multiply before becoming neurons. In the human brain, the process is extremely complex, involving billions of cells. In the fly brain, the process is much simpler, with around 200 stem cells for the entire brain. The smaller scale allows for a fine analysis of the neuronal cell division process from start to finish.

In flies, when the stem cell divides, it yields another stem cell and a progenitor cell. When this last one divides, it makes a so-called precursor cell that divides only once and gives rise to two neurons. Genes control this production process by telling the cells either to divide —and which particular type of cell to produce— or to stop dividing.

To this day, only a few of the genes that control this neuron development process have been identified and in this publication in Cell Reports, the scientists have characterized many more genes involved. Along the timeline of the neuron development process, the U-M team could precisely record which genes were involved and for how long.

In particular, at the progenitors’ stage, the scientists identified three genes that are important at this stage for defining what ‘kind’ of neuron each progenitor will make; these particular genes had never been described before in this context. They also validated previously known marker genes that are known to regulate the cell reproduction process.

When they applied their analysis technique to the other phases of the neuron development process, they also recorded the expression of additional genes. However, it is still unknown why these genes go up in expression at different steps of the neuron development process and what role they actually play in these different steps. “Now that many candidate genes are identified, we are investigating the roles they play in the neuron maturation and fate determination process,” says Cai. “We are also excited to explore other developmental timepoints to illustrate the dynamic changes of the molecular landscape in the fly brain.”

“This work provides rich information on how to program stem cell progeny into distinct neuron types as well as how to trans-differentiate non-neuronal cell types into neurons. These findings will have significant impact on the understanding of the normal brain development as well as on neuron regeneration medicine,” adds Cheng-Yu Lee, a Professor from the U-M Life Sciences Institute who collaborated with the Cai Lab.

The techniques

This study is mostly based on high-throughput single-cell RNA-sequencing techniques. The scientists took single cells from fruit flies’ brains and sequenced the RNA, generating hundreds of gigabytes of data in only one day. From the RNA sequences, they could determine the developmental stage of each neuron. “We now have a very good understanding of how this process goes at the RNA level,” says Michki.

The team also used traditional microscope observations to localize where these different RNAs are being expressed in the brain. “Combining in silico analysis and in situ exploration not only validates the quality of our sequencing results, but also restores the spatial and temporal relationship of the candidate genes, which is lost in the single cell dissociation process,” says Cai.

Photo on the left: A microscope image of one of the developing fruit fly brain lobes, stained for our cells of interest (white), and 4 different RNAs: mamo (yellow), bi (magenta), data (green), and a long non-coding RNA, cherub (cyan).

At the beginning of their study, the scientists analyzed the large data set with open-source software. Later, they developed a portal (MiCV) that eases the use of existing computer services and allows to test for repeatability. This portal can be utilized for cell and gene data analysis from a variety of organs and does not require computer programming experience. “Tools like MiCV can be very powerful for researchers who are doing this type of research for the first time and who want to quickly generate new hypotheses from their data,” says Michki. “It saves a lot of time for data analysis, as well as expenses on consultant fees. The ultimate goal is to allow scientists to focus more on their research rather than on sometimes daunting data analysis tools.” The MiCV tool is currently being commercialized.

The collaborators of this study are from the Dawen Cai lab at the University of Michigan Medical School as well as Dr. Cheng-Yu Lee, from the U-M Life Sciences Institute. The Cai lab is a member of the U-M Center for RNA Biomedicine. The team used two U-M core facilities, the Flow Cytometry Core and the Advanced Genomics Core. This work is supported by funding from the University of Michigan, including the MCubed program, Department of Cell and Developmental Biology’s IDEA Awards in Stem Cell Biology, and the MTRAC program.

Featured image: Figure to the left: Neurons in the fruit fly brain are made by passing through various differentiation states, and are segregated into unique subtypes based on the age and cell division number of their mother cell (progenitor). The complexity of this process is modelled in the diagram above. Different RNAs play a role in these neuron formation steps. This study identifies many RNAs that were not previously known to be involved in these processes, and helps us better understand how this complex neuron-generation process works at the molecular level. © University of Munich

Paper cited: Michki et al., The molecular landscape of neural differentiation in the developing Drosophila brain revealed by targeted scRNA-seq and multi-informatic analysis, Cell Reports (2021), DOI: https://doi.org/10.1016/j.celrep.2021.109039

Medicine

Scientists Discover “Jumping” Genes That Can Protect Against Blood Cancers (Medicine)

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New research has uncovered a surprising role for so-called “jumping” genes that are a source of genetic mutations responsible for a number of human diseases. In the new study from Children’s Medical Center Research Institute at UT Southwestern (CRI), scientists made the unexpected discovery that these DNA sequences, also known as transposons, can protect against certain blood cancers.

These findings, published in Nature Genetics, led scientists to identify a new biomarker that could help predict how patients will respond to cancer therapies and find new therapeutic targets for acute myeloid leukemia (AML), the deadliest type of blood cancer in adults and children.

Transposons are DNA sequences that can move, or jump, from one location in the genome to another when activated. Though many different classes of transposons exist, scientists in the Xu laboratory focused on a type known as long interspersed element-1 (L1) retrotransposons. L1 sequences work by copying and then pasting themselves into different locations in the genome, which often leads to mutations that can cause diseases such as cancer. Nearly half of all cancers contain mutations caused by L1 insertion into other genes, particularly lung, colorectal, and head-and-neck cancers. The incidence of L1 mutations in blood cancers such as AML is extremely low, but the reasons why are poorly understood.

When researchers screened human AML cells to identify genes essential for cancer cell survival, they found MPP8, a known regulator of L1, to be selectively required by AML cells. Curious to understand the underlying basis of this connection, scientists in the Xu lab studied how L1 sequences were regulated in human and mouse leukemia cells. They made two key discoveries. The first was that MPP8 blocked the copying of L1 sequences in the cells that initiate AML. The second was that when the activity of L1 was turned on, it could impair the growth or survival of AML cells.

“Our initial finding was a surprise because it’s been long thought that activated transposons promote cancer development by generating genetic mutations. We found it was the opposite for blood cancers, and that decreased L1 activity was associated with worse clinical outcomes and therapy resistance in patients,” says Jian Xu, Ph.D., associate professor in CRI and senior author of the study.

MPP8 thus suppressed L1 in order to safeguard the cancer cell genome and allow AML-initiating cells to survive and proliferate. Cancer cells, just like healthy cells, need to maintain a stable genome to replicate. Too many mutations, like those created by L1 activity, can impair the replication of cancer cells. Researchers found L1 activation led to genome instability, which in turn activated a DNA damage response that triggered cell death or eliminated the cell’s ability to replicate itself. Xu believes this discovery may provide a mechanistic explanation for the unusual sensitivity of myeloid leukemia cells to DNA damage-inducing therapies that are currently used to treat patients.

“Our discovery that L1 activation can suppress the survival of certain blood cancers opens up the possibility of using it as a prognostic biomarker, and possibly leveraging its activity to target cancer cells without affecting normal cells,” says Xu.

Xu is an associate professor of pediatrics at UT Southwestern and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research. Lead authors from the Xu lab include Zhimin Gu and Yuxuan Liu. Other collaborators include John Abrams and Alec Zhang from UT Southwestern, and Wenfeng An from South Dakota State University.

This work was supported by the National Institutes of Health (R01CA230631 and R01DK111430), CPRIT (RR140025, RP180504, RP180826 and RP190417), a Leukemia & Lymphoma Society Scholar award, an American Society of Hematology Scholar award, a Leukemia Texas Foundation research award, a Welch Foundation grant (I-1942), and donors to the Children’s Medical Center Foundation.

Featured image: Zhimin Gu, Ph.D., (left), postdoctoral fellow, Children’s Medical Center Research Institute at UT Southwestern (CRI), and a member of the Moody Medical Research Institute; Jian Xu Ph.D., associate professor, CRI. © UT Southwestern

Reference: Gu, Z., Liu, Y., Zhang, Y. et al. Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. Nat Genet (2021). https://www.nature.com/articles/s41588-021-00829-8 https://doi.org/10.1038/s41588-021-00829-8

Provided by UT Southwestern Medical Center

About CRI

Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas, the flagship hospital of Children’s Health. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology and metabolism. For more information, visit: cri.utsw.edu. To support CRI, visit: give.childrens.com/about-us/why-help/cri/.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Medicine

A New Co-driver In Breast Cancer (Medicine)

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UC researchers discover how two genes cooperate to cause cancer growth and can target treatments to stop it from happening

Cooperation is generally a good thing — working together to reach a goal.

But in the case of cancer, it can be detrimental. University of Cincinnati researchers have discovered that cooperation between two key genes drive cancer growth, spread and treatment resistance in one particularly aggressive type of breast cancer.

The good news is, though, with this knowledge, they can continue to aim their targeted treatments at these genes, singularly and together, to stop breast cancer in its tracks.

This study is published in the March 9 online edition of the journal Cell Reports.

Xiaoting Zhang, PhD, professor and Thomas Boat Endowed Chair in UC’s Department of Cancer Biology, director of the Breast Cancer Research Program and member of the University of Cincinnati Cancer Center.

“According to the American Cancer Society’s estimate, over 280,000 new cases of invasive breast cancer will be diagnosed in women in 2021,” explains Xiaoting Zhang, PhD, professor and Thomas Boat Endowed Chair in UC’s Department of Cancer Biology, director of the Breast Cancer Research Program and member of the University of Cincinnati Cancer Center, who led this research. “Like many other cancers, breast cancer cells are fueled by mutations and overproduction of ‘driver’ genes, which lead the process of cancer development.”

He says one of these genes, called HER2 (human epidermal growth factor receptor 2), accounts for about 20% of all human breast cancer cases, and while there are some therapies to target it, unwanted side effects and treatment resistance often occur in patients, causing relapse.

“There are about a dozen additional genes, including one called MED1, located within the same chromosomal region where HER2 and other genes are multiplied in breast cancer, but it’s not known whether any of these genes are simply ‘passenger’ genes, and let HER2 to do the driving, or actually collaborate with the gene to play significant roles in the development, spread and treatment resistance of this type of breast cancer.”

To investigate this, the team created an animal model with an overproduction of both genes, HER2 and MED1, in the mammary gland.

This helped researchers discover the key role MED1 played in helping HER2 promote breast tumor growth, spread and treatment resistance. They found that the genes could in fact work with each other to further speed up their production and activities, which in turn promotes rapid cell multiplication, movement and invasion to spread cancer and cause treatment resistance.

Breast cancer cells. Photo courtesy of the National Cancer Institute.

Zhang adds that previous research has shown that MED1 has a role in treatment resistance in another type of breast cancer, ER+ (estrogen receptor positive). This UC study established MED1 as a key driver in the development and treatment resistance of two major kinds of breast cancer.

“Our findings suggest that targeting MED1, alone and in combination with current therapies, could be an effective treatment strategy for nearly 90% of breast cancer patients in clinics and combat treatment resistance to two widely used breast cancer therapies,” Zhang says.

Zhang and his team have already developed a treatment targeting MED1 specifically in tumors, using RNA nanotechnology similar to that used for the COVID-19 vaccines, and have observed positive outcomes. This technology is currently patent pending.

Creating foundations for future research, careers

Yongguang Yang, PhD, first author on this study and a research associate in Zhang’s lab, says the work he’s done on studying the roles of these genes in cancer and treatment resistance is eye-opening and takes a true “teamwork” approach.

“Working together as a team is very important in this process, as collaborations with the basic cancer biology researchers, clinical teams and physicians ensure our access to their unique insights and firsthand clinical experience, data and samples,” he says. “These findings are exciting and relate very closely to how this cancer impacts people. This new animal model we created has a wide range of future applications and will allow us to continue to study basic molecular mechanisms of this type of breast cancer to find and test new therapies.”

“The new model we created has a wide range of future applications and will allow us to study basic molecular mechanisms of this type of breast cancer to find and test new therapies.” 

—  Yongguang Yang, PhD, first author, research associate in Zhang’s lab

“It was very exciting to be able to not only conduct my graduate studies on something so innovative and impactful as identifying new ways that breast cancers function, but also to develop potential applications for the future of cancer treatment,” adds co-author, Marissa Leonard, PhD, a recent doctoral graduate of the cancer and cell biology program at UC. “One or the other is often seen in research labs, but doing both is something I would consider a rare opportunity.”

“The scientific experience, knowledge and writing skills I gained from Dr. Zhang’s lab and our graduate program at UC have greatly broadened my horizons and allowed me to familiarize myself with a wide range of scientific concepts,” says Leonard, who is now a medical writer. “These broad, laboratory-based skill sets bode well for many different career paths, too, whether that includes continued research, medical writing, regulatory science, patent law, teaching or others.” 

Authors and collaborators on this study also include UC breast oncologists Elyse Lower, MD, and Mahmoud Charif, MD; pathologist Jiang Wang, MD, PhD; cancer biology researcher Jun-Lin Guan, PhD, and his lab members Syn Yeo, PhD, and Mingang Hao, PhD; Zhenhua Luo, PhD, of the Cincinnati Children’s Hospital Medical Center; and Gregory Bick, PhD, and Chunmiao Cai, PhD, from Zhang’s laboratory.

This research was supported by the National Cancer Institute (R01CA197865 and R01CA229869), Ohio Cancer Research Seed Grant, University of Cincinnati Cancer Center and Ride Cincinnati Awards. Researchers cite no conflict of interest.

Featured image: Xiaoting Zhang © UC

Provided by University of Cincinnati

Biology

X Marks The Spot: How Genes On The Sex Chromosomes Are Controlled (Biology)

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Researchers from the University of Tsukuba find that genes on the X chromosome in male fruit fly germ cells are regulated differently from other cells

Because human females have two X chromosomes and males have one X and one Y, somatic cells have special mechanisms that keep expression levels of genes on the X chromosome the same between both sexes. This process is called dosage compensation and has been extensively studied in the fruit fly Drosophila. Now, researchers at the University of Tsukuba (UT) continued work with Drosophila to show that dosage compensation does not occur in the germ cells of male flies.

In an article published in Scientific Reports, the UT researchers investigated this phenomenon in fly primordial germ cells (PGCs), which are present in embryos and are the precursor cells to what ultimately become sperm and eggs in adults. Previous reports on dosage compensation in this cell type were controversial.

Genetic research in somatic cells has shown that expression of X-linked genes in male fruit flies is upregulated to reach equivalent levels to that of their female counterparts. A group of proteins, called the male-specific lethal (MSL) complex, is responsible for carrying out this role. These findings made the UT group interested in if this mechanism also occurs in the male germ cells. Distinct molecular events occur in the PGCs during embryonic development between male and female fruit flies. Because results shown in earlier publications did not align, the researchers chose to address their main question differently.

“The MSL complex leaves a signature mark, called acetylation, on a specific amino acid of the histone H4 protein of the X chromosome,” says Professor Satoru Kobayashi, senior author of the study. “The acetyl group being added tells the cell to express the X-linked genes at a higher level, which results in dosage compensation.”

To address their questions, the researchers used a process called transcriptome analysis to compare gene expression levels between male and female fruit fly PGCs. They also examined the histone H4 protein to determine if acetylation had occurred.

“We found that X-linked gene expression in male PGCs was about half that of female PGCs,” describes Professor Kobayashi. “We also could not detect the acetylation signature of the MSL complex.”

The authors also determined that the main components of the MSL complex are only present in very low amounts in the fly PGCs. Interestingly, they then created transgenic flies that were engineered to express higher levels of the MSL complex proteins. Male PGCs in these flies showed greater activation of X-linked genes, as well as the acetylation signature.

The researchers believe that the findings of this study have high biological significance, possibly suggesting that the absence of dosage compensation affects sex determination in Drosophila PGCs. This work provides novel insight that will be crucial for further investigation of embryo development and germ cell maturation.

Reference: Ota, R., Hayashi, M., Morita, S. et al. Absence of X-chromosome dosage compensation in the primordial germ cells of Drosophila embryos. Sci Rep 11, 4890 (2021). https://www.nature.com/articles/s41598-021-84402-7 https://doi.org/10.1038/s41598-021-84402-7

Provided by University of Tsukuba

Medicine

Gene That Helps Control Egg’s Journey Sheds Light On Why Ectopic Pregnancy May Occur (Medicine)

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Study details the first evidence of gene regulation in the transit of eggs from the ovaries to the uterus in mammals

Ectopic pregnancy is one of the most common prenatal complications, yet the cause of the condition remains unknown. Now researchers at the Wellcome Sanger Institute have pinpointed a gene in mice that plays a key role in the egg’s journey from the ovary to the uterus. When the gene Adgrd1 was deleted, female mice became infertile because the eggs remained stuck in the fallopian tubes.

The study, published today (23 February 2021) in Nature Communications, details the first evidence of gene regulation in the transit of eggs from the ovaries to the uterus in mammals. The findings highlight Adgrd1 as a promising target for future studies in humans, in order to search for genetic mutations or anomalies that may help to explain why ectopic pregnancy occurs.

Each month, a single egg is released from one of a woman’s ovaries and travels to the uterus via the fallopian tubes (also known as oviducts). The egg ‘pauses’ at a certain location, called the ampullary-isthmic junction, for several days. If sperm are present, this is where fertilization occurs. The egg then continues its journey and, if it has been fertilized, will implant into the wall of the uterus. This process is common to many mammal species, including mice.

Ectopic pregnancies occur when a fertilized egg implants and develops outside of the uterus, usually in one of the fallopian tubes. This is known as a tubal pregnancy and it is not possible to save the pregnancy once this occurs*. Ectopic pregnancy affects one to two per cent of all conceptions in the United States and Europe, and is the most common cause of pregnancy-related death in the first trimester.

Movement of the egg is controlled by several factors, including tiny hairs called cilia on the surface of the fallopian tubes which wave the egg towards the uterus, muscle contractions, and the flow of oviductal fluid. But the biology of the egg’s journey is not fully understood, particularly how the ‘pause’ at the ampullary-isthmic junction is regulated.

In this study, researchers at the Wellcome Sanger Institute set out to identify genes required for female fertility whose function was not fully understood. They analysed the International Mouse Phenotyping Consortium database, which contains data on mice that have had certain genes suppressed or ‘switched off’, and identified Adgrd1 as a gene of interest.

When they examined female mice that lacked a functional Adgrd1 gene, they observed that although the mice ovulated normally and fertilisation took place, the eggs could not move past the ampullary-isthmic junction and implanted outside of the uterus**.

To find out why, they investigated the movement of cilia in the fallopian tubes, muscle contractions and the flow of oviductal fluid. Scientists at Genentech, a member of the Roche Group, conducted a genetic screen to determine the molecular mechanisms at play.

The team concluded that the suppression of Adgrd1 activity affected the flow of oviductal fluid, preventing the egg from continuing its journey to the uterus after the ‘pause’ at the ampullary-isthmic junction.

“The flow of oviductal fluid in mammals is somewhat counterintuitive, in that it flows in the opposite direction to the egg’s direction of travel. What we’ve discovered in this study is that the strength of this flow is normally downregulated by the Adgrd1 gene. But when Adgrd1 is suppressed, the flow is not reduced and the egg cannot seem to move past the ampullary-isthmic junction.”

— Dr Enrica Bianchi, first author of the study from the Wellcome Sanger Institute

“The molecular cues that dictate G protein-coupled receptor signalling and biological functions still remain poorly understood, despite these proteins represent main drug targets. The identification of Plxdc2 as an activating ligand for Adgrd1 sheds light on the biology of this previously orphan receptor and opens new avenues for the treatment of ectopic pregnancy.”

— Nadia Martinez-Martin, a senior author of the paper from biotechnology company Genentech, a member of the Roche Group

Though this study was conducted in mice, a species in which ectopic pregnancy does not occur, the reproductive biology of humans, mice and other mammals share many of the same mechanisms. The next step is to conduct further studies in humans, to see if the role of Adgrd1 is the same and whether mutation or loss of function of this gene correlates with incidence of ectopic pregnancy.

“Though several risk factors of ectopic pregnancy are known, the precise genetic and molecular mechanisms behind the condition have remained unclear. The discovery of the function of Adrgd1 in oviductal fluid regulation, and the consequences of its absence, provides an important clue for researchers studying the causes of ectopic pregnancy in future.”

— Dr Gavin Wright, senior author of the study from the Wellcome Sanger Institute

Featured image credit: adobestock

Reference: Bianchi, E., Sun, Y., Almansa-Ordonez, A. et al. Control of oviductal fluid flow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit. Nat Commun 12, 1251 (2021). https://www.nature.com/articles/s41467-021-21512-w https://doi.org/10.1038/s41467-021-21512-w

Provided by Wellcome Sanger Institute