PDS5A

To function properly, the genetic material is highly organized into loop structures that often bring together widely separated sections of the genome critical to the regulation of gene activity. Scientists now address how these loops can help repress or silence gene activity, with potentially far-reaching effects on human health. The blueprint for human life lies within the DNA in the nucleus of each of our cells. In human cells, around six and a half feet of this genetic material must be condensed to fit inside the nucleus. DNA condensation is not random. To function properly, the genetic material is highly organized into loop structures that often bring together widely separated sections of the genome critical to the regulation of gene activity. In a new paper published in Nature Communications, USC Stem Cell scientists from the laboratory of Oliver Bell address how these loops can help repress or silence gene activity, with potentially far-reaching effects on human health. "A carefully orchestrated regulatory machinery is required to ensure every cell in the body is expressing its correct gene set to exert its dedicated function," said the study's first author Daniel Bsteh, who began the research at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), and completed it at the Keck School of Medicine of USC during his PhD. He is currently the Liquid Biopsy Core Manager at the USC Norris Comprehensive Cancer Center. In the study, Bsteh and his colleagues specifically examined developmental genes that are repressed by molecules known as Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). PRC1 and PRC2 are regulators that prevent developmental genes from becoming activated at the wrong time or in the wrong cell, which has been shown to cause changes in cellular identity, leading to developmental defects, or transformation into cancer cells. When PRC1- and PRC2-repressed genes come together, the genome forms loops. Loops are known to play a role in activating genes, but it has been more challenging to study how loops might help repress genes. This is because of the interdependence of loops with a different type of gene repressing mechanism known as histone modifications. Through a genetic screen conducted in mouse embryonic stem cells, the scientists identified a protein, PDS5A, that modifies loops without affecting histone modifications. This enabled Bsteh and colleagues to specifically study the effects of loops and 3D genome organization on gene silencing. The loss of PDS5A disrupted the loops -- and therefore the long-range interactions between repressed developmental genes. Further, looping genes together maintains the silent state. When PRC1- and PRC2-repressed genes are physically separated, eliminating the loops, normally silent genes become activated in aberrant ways. "PDS5A is a subunit of a larger protein complex called cohesin, which is the master regulator of 3D genome organization," said Bell, an assistant professor of biochemistry and molecular medicine, and stem cell biology and regenerative medicine, and a member of the USC Norris Comprehensive Cancer Center. "Cohesin mutations are known to drive several human diseases, including developmental disorders and cancer. What's striking about our discovery is that it reveals a dependence of PRC 1 and PRC 2 activity on the precise regulation of 3D genome organization by cohesin, suggesting that 'cohesinopathies' may be linked to aberrant developmental gene silencing." Additional authors include Hagar F. Moussa, Georg Michlits, Ramesh Yelagandula, Jingkui Wang, and Ulrich Elling from the IMBA. Support for this research came from the Austrian Academy of Sciences, the New Frontiers Group of the Austrian Academy of Sciences (grant NFG-05), the Human Frontiers Science Program Career Development Award (CDA00036/2014-C), and startup funding from the USC Norris Comprehensive Cancer Center.

STAMFORD, Conn., Feb. 28, 2023 (GLOBE NEWSWIRE) -- GeneDx (Nasdaq: WGS), a leader in delivering improved health outcomes through genomic and clinical insights, today announced its contributions to eight posters, one platform presentation and one symposium session to be released at the upcoming 2023 American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting. The announcement coincides with Rare Disease Day and is just the latest example of the company’s dedication to eradicating the multi-year diagnostic odyssey faced by many families seeking clinical diagnoses for critically ill patients. GeneDx is a leader in rare disease diagnosis and has spent the last 20 years building one of the largest rare disease datasets in the genomics industry, including data from more than 400,000 clinical exomes. These data play a critical role in the company’s research -- and in the insights it delivers to providers -- to enable the delivery of informed, patient-centered care. It also supports the identification, discovery and development of creating therapeutics to manage and treat rare genetic diseases. “While today is officially recognized as Rare Disease Day, every day is rare disease day for us as we work tirelessly to shorten and ultimately end the diagnostic odyssey,” said Katherine Stueland, GeneDx President and CEO. “With the increasing focus on patients with rare disease, we’re proud to bolster the medical community’s ability to diagnose disease more accurately and rapidly. Our research contributions are evidence of our investment into unlocking and advancing the power of genomic information to become the standard of care in diagnosing and treating rare disease.” The research and collaborations being shown at ACMG are just the latest demonstration of the company’s continued success in leveraging genetic data and technology to generate clinical insights that lead to improved and faster diagnoses, new and better patient treatments and improved outcomes. GeneDx’s presence at ACMG on March 15 at the Salt Palace Convention Center in Salt Lake City, Utah, is as follows: ORAL PRESENTATION RESEARCH COLLABORATIONS Genomic Uniform-screening Against Rare Diseases in All Newborns (GUARDIAN): Presented by Dr. Wendy Chung, MD, PhD, Overall Study Principal Investigator, Columbia University: [Part of the R. Rodney Howell Symposium, March 15, 2023, 10:45 AM MT] Developing a Framework for Sequence Variant Interpretation for Multiple X-linked Inborn Errors of Metabolism: The ClinGen IEM Working Group Experience In partnership with ClinGen [March 17, 2023 3:30 PM MT] GENEDX POSTER PRESENTATION RESEARCH COLLABORATIONS In collaboration with Tara Wenger and Alexandra Keefe of University of Washington: Parental Perspectives on SeqFirst Neonatal Rapid Genome Sequencing SeqFirst: Impact of a Precise Genetic Diagnosis on End-of-Life Decision Making in the NICU POSTER PRESENTATIONS SHOWCASING STUDIES LED BY GENEDX Diagnostic Yield of Copy Number Variants by Exome Sequencing versus Chromosomal Microarray Four Cases of Mosiac Triploidy Identified by Trio Exome Sequencing POSTER PRESENTATION RESEARCH COLLABORATIONS: RARE DISEASE DISCOVERY AND CONTRIBUTIONS TO PROFESSIONAL DECISION-MAKING BODIES Rare Disease Discovery: De novo missense variants in ZBTB47 cause a neurodevelopmental phenotype of developmental delays, seizures, and possible movement abnormalities Mutation of Cohesin Release Factors WAPL, PDS5A, and PDS5B Defines a New Class of Cohesinopathies Professional Decision-Making Bodies: ATM and PALB2 Variant Curation Guidelines Progress Update: ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel In partnership with ClinGen The ClinGen ENIGMA BRCA1/2 Expert Panel: a dynamic framework for evidence-based recommendations to improve classification criteria for variants in BRCA1/2 In partnership with ClinGen About GeneDx GeneDx delivers personalized and actionable health insights to inform diagnosis, direct treatment and improve drug discovery. The company is uniquely positioned to accelerate the use of genomic and large-scale clinical information to enable precision medicine as the standard of care. GeneDx is at the forefront of transforming healthcare through its industry-leading exome and genome testing and interpretation, fueled by one of the world’s largest rare disease data sets. For more information, please visit genedx.com and connect with us on LinkedIn, Facebook, and Instagram. Media contact Stephanie Kahan Press@genedx.com Investor contact Tricia Truehart Investors@genedx.com