PTF1A

There's a potential new therapeutic target for Crohn's disease, a large study says risk of myocarditis is much higher after COVID-19 than vaccination and a mouse study sparks hope for a potential cure for childhood brain tumors. Here's a look at just some of this week's most intriguing research news. Potential New Therapeutic Target for Crohn's Disease Researchers with Massachusetts General Hospital unraveled new mechanisms behind Crohn's disease. Chromatin is a combination of DNA and proteins that form chromosomes, and this structure can affect gene expression. Certain chromatin "readers" play a part in monitoring chromatin's response to the environment. The research team found that mutations within one reader, Speckled Protein 140 (SP140), were linked with an increased risk of certain immune diseases, including Crohn's disease. They published their research in the journal Cell. Kate L. Jeffrey, Ph.D., principal investigator of immunology at MGH and an associate professor of medicine at Harvard Medical School, said, "The work broadens our understanding of epigenetics in health - or the physical changes in cells' DNA structure that affect the expression of genes in response to environmental cues. Importantly though, it revealed how dysregulation of epigenetic factors drive diseases such as Crohn's that are rising in incidence because of the complex interplay of genes plus environment." Expression of SP140 is uniquely restricted to immune cells, including macrophages. These immune cells engulf and kill microorganisms, remove dead cells and stimulate other immune cells into action. They found that SP140 represses topoisomerases (TOP), enzymes that assist DNA in untangling during replication. Loss of SP140 in mice and humans allows uncontrolled TOP activity, which leads to abnormal gene expression and the killing of bacteria by macrophages that lead to intestinal abnormalities. Inhibiting TOP halted these defects in a mouse model. Myocarditis Risk Much Higher After COVID-19 Infection Versus After Vaccine In rare situations, cases of heart inflammation, or myocarditis, were observed in people after receiving a COVID-19 vaccine. A new study of almost 43 million people 13 years and older who received at least a single dose of a COVID-19 vaccine in England found that the risk of myocarditis in unvaccinated people after COVID-19 infection was 11 times higher. This is compared to people who developed myocarditis after receiving a vaccine or booster. The data looked at people who received the shots between Dec. 1, 2020, and Dec. 15, 2021. Investigators conducted the research at the University of Oxford. The vaccines involved were Pfizer-BioNTech, Moderna and the AstraZeneca-University of Oxford shots. How Enhancer Mutations Cause Disease Researchers from the Center for Genomic Regulation have identified mutations in specific gene sequences known as enhancers that are associated with pancreatic malformations. The sequence is dubbed EnhP, and mutations in this particular DNA sequence lead to pancreas malformations. In mice, these mutations caused underdeveloped pancreas and insulin-deficient diabetes. They don't appear to disrupt the DNA sequence of a gene. Enhancers appear hundreds of thousands of times within the genome and act as switches to turn on transcription of their target genes in the correct tissues. The researchers believe these enhancer mutations may explain diseases where laboratory assays have yet to identify gene mutations that cause these diseases. The only role of EnhP is to activate a cluster of enhancers that regulate PTF1A, the pancreas-associated transcription factor 1a, in the first cells that form the pancreas during fetal development. Potential Cure for Childhood Brain Tumors Investigators at the Karolinska Institute, Massachusetts General Hospital and the Harvard Stem Cell Institute have identified what they call a potentially curative treatment of neuroblastoma in mice when combined with chemotherapy. The research group demonstrated that DHODH blockers appear to cure neuroblastoma in mice if given with chemotherapy. In other studies, DHODH blockers have been shown to be well tolerated in humans for other diseases. In analyzing patient data from more than 600 children with neuroblastoma, they found that tumors with high levels of DHODH were more aggressive and deadly. They utilized a DHODH blocker named Brequinar. The drug decreased the activity of the MYCN gene, which drives tumor growth. But after treatment, the tumors started growing again. They then combined Brequinar with chemotherapy, which cured the mice with neuroblastoma. Treatment Eradicated Mesothelioma Tumors Within Days Working in mice, researchers with Rice University and Baylor College of Medicine used a cytokine "drug factory" implant and a checkpoint inhibitor to eliminate advanced-stage mesothelioma tumors. The implants are tiny beads, no larger than the head of a pin, that produce drugs. The research team implanted them next to tumors, where the beads then produced continuous, high doses of interleukin-2 (IL-2), a compound that activates white blood cells. The alginate beads carry tens of thousands of genetically engineered cells designed to manufacture IL2 and appeared to eradicate the tumors in less than a week. They used the beads in conjunction with an anti-PD-1 checkpoint inhibitor. The researchers have had discussions with the U.S. FDA and expect to begin running a clinical trial using the beads late next year. "The preclinical data reported in our latest manuscript helped justify initiating a second clinical trial for patients suffering from mesothelioma and other lung cancers with pleural metastasis," Omid Veiseh, Ph.D., a bioengineer at Rice who invented the beads, said. "We have held meetings with the FDA and expect to initiate a second trial for this patient population in the latter half of 2023."

In the vast majority of diseases caused by mutations in a single DNA sequence, the disruption of a gene is to blame. However, many non-coding elements in the genome, which inhabit what is sometimes known as the 'dark genome' are also thought to play a role in disease. New research finds the most clear-cut example to date, identifying a genetic switch that, when mutated, causes severe pancreatic deformation and neonatal diabetes. Researchers at the Centre for Genomic Regulation (CRG) have identified a DNA sequence that is crucial for pancreatic differentiation and function -- and for the first time -- describe how it works. Patients with mutations in a DNA sequence -- which they coin EnhP -- develop pancreas malformations. It is the most clear-cut example to date of an inherited disease that is caused by mutations that do not disrupt the DNA sequence of a gene. Disorders?caused by mutations in a single DNA sequence, for example Huntington disease or sickle cell anaemia, are known as monogenic diseases. In the vast majority of cases, such mutations disrupt a protein-coding gene. In this case, the mutations in EnhP disrupt a single "enhancer" instead of a single gene. Our genomes contain hundreds of thousands of DNA elements that are thought to act as enhancers. These enhancer DNA sequences act as switches to turn on the transcription of their target genes in the right tissues. According to the authors of the study, published today in Developmental Cell, EnhP is by no means the only enhancer defect to cause disease. Mutations in enhancers may be the cause of a monogenic disease in many patients in which laboratory tests have failed to disclose causal gene mutations. Understanding the role of enhancers in disease could change how we practice medicine. "Clinical genetics is shifting from a focus on sequencing protein-coding genes to sequencing whole genomes. It is now theoretically possible to discover disease-causing mutations that lie outside of traditional areas of the genome, although it is still challenging to discern which parts of the genome are truly vulnerable to mutations," explains Dr. Jorge Ferrer, senior author of the study, Coordinator of the Medical Genomics Transversal Programme at the CRG and Group Leader at CIBERDEM. The researchers had previously discovered EnhP when studying developmental disorders across ten different families. In collaboration with a team in Exeter, United Kingdom, they had found that mutations in the enhancer were the most common cause of pancreatic agenesis, a rare congenital disorder causing loss of pancreatic tissue and neonatal diabetes. In this study, researchers developed on their previous work to explain why this particular enhancer is vulnerable to disease-causing mutations. Using CRISPR, the team genetically-engineered mouse models to study the effects of the enhancer. Mice lacking both copies of EnhP were born with a severely underdeveloped pancreas and insulin-deficient diabetes. They also studied human stem cells in vitro. They show that EnhP works by increasing rates of transcription of a nearby gene known as the pancreas associated transcription factor 1a (PTF1A). More specifically, the study revealed that EnhP's only role is to activate a whole cluster of enhancers that also regulate PTF1A in the very first cells that form the pancreas during fetal development. When these other enhancers are activated and PTF1A transcription is turned on, this sets in motion a cascade of molecular events that lead to the formation of normal pancreatic cells. "We show that enhancers operate in a hierarchical manner, and this one sits straight at the top, says Dr. Ferrer. This is a new concept, and it solves a paradox of how mutations in a single enhancer can be catastrophic despite the existence of multiple other enhancers regulating the same gene. This is not just about this particular enhancer or disease, there are probably many other enhancers with this particular function in the human genome. Finding them will help us understand which enhancers are vulnerable to mutations that cause various other monogenic diseases." The discovery also has ramifications for efforts to generate insulin-producing beta cells in laboratory conditions. Cell transplantation is a feasible option for diabetic patients, but the demand for functional cells from dead donors far outstrips supply. Growing beta cells in culture would be one way of addressing this challenge, but these rarely share the same functional features as normal human beta cells. This is in part because we don't know the mechanisms required for proper differentiation. "EnhP sparks a molecular program that is needed for proper formation of human beta cells. This knowledge can be harnessed to improve laboratory conditions to create beta cells" concludes Dr. Ferrer. This research was supported by the Spanish Ministry of Science and Innovation, the Wellcome Trust, CIBERDEM and the European Research Council. The work was co-led by first co-authors Irene Miguel-Escalada, Miguel Ángel Maestro, Diego Balboa and senior author Jorge Ferrer.