We are thrilled to celebrate the promotion of Core Member Melike Lakadamyali, Ph.D. to Professor of Physiology. Please join us in congratulating Dr. Lakadamyali on this well-deserved achievement!
To learn more about Dr. Lakadamyali, please visit her lab website: https://www.lakadamyali-lab.com/.
We are thrilled to celebrate the promotion of Core Member Eric Joyce, Ph.D. to Associate Professor of Genetics. Please join us in congratulating Dr. Joyce on this great achievement! We are excited to watch as your career continues to grow!
To learn more about Dr. Joyce, please visit his lab website: https://ericjoycelab.com/.
Congratulations to Epigenetics Institute Co-Director Marisa Bartolomei, PhD on receiving the 2024 March of Dimes Richard B. Johnston, Jr., MD, Prize! Please see the full announcement below, and click here for more information about the Prize.
March of Dimes, the leading organization fighting for the health of moms and babies, is pleased to announce Marisa Bartolomei, PhD, as the recipient of the 2024 March of Dimes Richard B. Johnston, Jr., MD Prize. This annual award honors an outstanding scientist who has advanced the science that underlies our understanding of pregnancy, birth, and prenatal development. Dr. Bartolomei is a Co-Director of the Epigenetics Institute at the University of Pennsylvania’s Perelman School of Medicine, where she is also the Perelman Professor of Cell and Developmental Biology.
Over her 30-year career, Dr. Bartolomei has made instrumental discoveries on the function and expression of certain genes, called imprinted genes. These genes, whose proper expression is critical for healthy pregnancy and fetal development, can be severely affected by numerous factors, including environmental exposures throughout life and pregnancy.
“Dr. Bartolomei’s astounding body of work on how the abnormal expression of imprinted genes can lead to severe developmental errors and devastating diseases for babies has brought us closer to the development of critical diagnostic and therapeutic interventions,” said Dr. Emre Seli, Chief Scientific Officer at March of Dimes. “I am incredibly excited and honored to present Dr. Bartolomei with this award. She exemplifies the spirit of the prize through her dedication to bridging the divide between science at the bench and medicine at the bedside so the work we do today can improve outcomes for moms and babies tomorrow.”
This award, named in honor of Dr. Johnston, Professor Emeritus of Pediatrics at the University of Colorado and a former Medical Director at March of Dimes, carries a cash award and was created as a tribute to Dr. Jonas Salk, developer of the polio vaccine. It is part of March of Dimes’ research strategy to address the multi-faceted nature of the maternal and child health crisis. To date, six recipients have gone on to win the Nobel Prize in Physiology or Medicine.
Throughout her career, Dr. Bartolomei’s research has addressed the epigenetic mechanisms of genomic imprinting and germline reprogramming as well as the impact of early environmental exposures on epigenetic gene regulation. Imprinted genes, unlike traditional genes, normally express only one copy (one from the mother or one from the father). When things go wrong, as with an epigenetic mutation, these genes will express either both or neither of its copies. This can cause devastating developmental errors during pregnancy that lead to serious disease.
Dr. Bartolomei succeeded in identifying one of the first imprinted genes in 1991. Her later work identified connections between imprinted genes and early developmental disorders like Beckwith-Wiedemann Syndrome, which causes babies to grow too big in the womb and predisposes them to cancer, and Silver-Russell Syndrome, which causes babies to grow too slowly in utero. Her continued work in other related areas has improved our understanding of gene reprogramming, defects in expression, and the impact of environmental exposures, like Bisphenol A (BPA) and phthalates, on healthy development. This work has revealed the critical role of imprinted genes in healthy development, opening new possibilities to prevent and cure disease.
“We are truly just getting started with imprinted genes,” Dr. Bartolomei said. “As the scientific community continues to discover the vital role these genes have in development, others are doing work on new screening tests, therapeutics, and interventions to ensure that imprinted genes are expressed properly, and if they are not, to invent treatments that can be administered to avoid the worst outcomes. And for me, this award is truly exhilarating—when I look at past awardees, some of whom have been important mentors and influenced my career, it’s really special.”
March of Dimes will present the award to Dr. Bartolomei at the 2024 Annual Meeting of the Society for Reproductive Investigation in Vancouver, British Columbia on March 16, 2024.
Dr. Bartolomei received her BS from the University of Maryland and PhD from the Johns Hopkins University School of Medicine. She completed postdoctoral training at Princeton University with Dr. Shirley Tilghman, President Emerita Princeton University. In 1993, Dr. Bartolomei was appointed as Assistant Professor at the University of Pennsylvania, rising to Professor in 2006. She was elected as a Fellow of the American Association for the Advancement of Science in 2014 and is a Member of the National Academy of Sciences.
Congratulations to Core Member Arjun Raj, PhD, who was recently awarded the 2023-24 George H. Heilmeier Faculty Award for Excellence in Research! He was selected for this award to recognize his work “pioneering the development and application of single-cell, cancer-fighting technologies.”
The Heilmeier Award honors a Penn Engineering faculty member whose work is scientifically meritorious and has high technological impact and visibility.
Congratulations to Rexxi Prasasya, PhD, who has been awarded a K99 Pathway to Independence Award. Dr. Prasasya, a Research Associate in the Bartolomei Lab, received this award for her project titled “Molecular determinants of sex-specific DNA methylation signature acquisition in the mammalian germline.”
She plans to use this award to continue her research into elucidating how the most sexually dimorphic epigenetic marks, DNA methylation, is established in the germ cells. Aberrant DNA methylation in gametes is associated with idiopathic infertility, poorer outcomes during fertility treatment, and can be deleterious to early embryonic development. Using various mouse genetic models, Dr. Prasasya will be investigating intracellular and extracellular cues that instruct the patterning of DNA methylation in oocytes and sperm.
The study, led by Tong Wang, MD/PhD student in the Kohli Lab, demonstrates a new technique that requires smaller DNA samples for testing and opens up potential new opportunities for next-generation diagnostics. Read the full article at Penn Medicine news or below.
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Researchers from the Perelman School of Medicine at the University of Pennsylvania have invented a new way to map specific DNA markings called 5-methylcytosine (5mC) which regulate gene expression and have key roles in health and disease. The innovative technique allows for scientists to profile DNA using very small samples and without damaging the sample which means it can potentially be used in liquid biopsies (testing for cancer markers in the bloodstream) and early cancer detection. Additionally, unlike current methods, it also can clearly identify 5mC without confusing it with other common markings. The new approach, named Direct Methylation Sequencing (DM-Seq), is detailed in a Nature Chemical Biology article today.
Beyond the primary bases of DNA (adenine, cytosine, guanine, and thymine), there is an added layer of information in DNA modifications that control what genes are “on” or “off” in any given cell type. 5mC is considered to be one of the most important of these modifications, as it is the most common type of DNA modification in all mammals and is known for silencing certain genes.
“5mC can act as a fingerprint for cell identity, so it’s important for scientists to have the power to isolate 5mC and only 5mC,” said Rahul Kohli, MD, PhD, an associate professor of Biochemistry and Biophysics at Penn Medicine and a senior author of the study. “DM-Seq uses two enzymes to map 5mC and can be applied to sparse DNA samples which means it could be used, for example, in blood tests that look for DNA released into the blood from tumors or other diseases tissues.” The study was led by Tong Wang, an MD/PhD student in Kohli’s lab.
DNA modifications such as 5mC function as epigenetic (reversible, environmentally-caused) regulators that alter how DNA is read. 5mC involves the attachment of a small cluster of atoms called a methyl group at a particular site on a cytosine, also known as the letter “C” in the four-letter DNA alphabet. The presence of this modification can impede the expression of nearby DNA through direct and indirect mechanisms.
The DNA that is rendered inactive by 5mC includes protein-encoding genes whose activity may not be appropriate in a given cell type at a given stage of life, as well as virus-like elements in DNA that should always be suppressed. Unsurprisingly, the abnormal absence or excess of 5mC can lead to abnormal gene expression, which can drive diseases such as cancers. Certain abnormal patterns of 5mCs are considered signatures of some cancers—which underscores the importance of having an accurate and specific 5mC mapping method.
Methods for mapping 5mC use chemicals or enzymes that react with 5mC and normal unmodified cytosine in different ways, allowing the two to be distinguished. But the traditional method, bisulfite sequencing (BS-Seq), is significantly damaging to DNA, and fails to distinguish between 5mC and another important type of methylation called 5-hydroxymethylcytosine (5hmC). More recently developed methods also have shortcomings including the requirement for relatively large amounts of DNA.
DM-Seq utilizes two enzymes that can modify DNA, a designer DNA methyltransferase and a DNA deaminase, which together can detect 5mC directly and specifically. It also is sensitive enough to be done with nanogram amounts of DNA, which makes it suitable for liquid biopsy applications.
The researchers performed DM-Seq on glioblastoma-type brain tumor samples and demonstrated that, in comparison with traditional BS-Seq, DM-Seq was better able to distinguish 5mC from 5hmC at key sites on the genome where methylation levels can be used to predict patient outcomes.
The researchers also compared DM-Seq to another new, emerging 5mC-sequencing technique called TAPS, which is being explored for potential applications in cancer diagnostics, showing that the latter has a previously undiscovered drawback that reduces its 5mC-detection sensitivity.
“These findings highlight ways in which direct detection of 5mC from DM-Seq, rather than traditional sequencing methods, could advance efforts to use epigenetic sequencing for prognostic purposes in cancer care,” Kohli said.
Along with Kohli and Wang, other Penn authors included Johanna Fowler, Laura Liu, Christian Loo, Meiqi Luo, Emily Schutsky, Kiara Berríos, Jamie DeNizio, Saira Montermoso, Bianca Pingul, MacLean Nasrallah, and Hao Wu.
The research was supported by the National Institutes of Health (R01-HG10646).
Congratulations to Raj Jain, MD, on this fantastic award! Please read the full news release below or at Penn Medicine News. To learn more about Dr. Jain’s work, please visit his Lab Website.
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Historically, scientists have studied how cells develop and give rise to specialized cells, such as heart, liver, or skin cells, by examining specific proteins. However, it remains unclear how many of these proteins influence the activity of hundreds of genes at the same time to turn one cell type into another cell type. For example, as the heart develops, stem cells and other specialized cells will give rise to heart muscle cells, endothelial cells (lining of blood vessels), smooth muscle cells, and cardiac fibroblasts. But the details of this process remain mysterious.
As a result of a $6 million, seven-year grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH), researchers from the Perelman School of Medicine at the University of Pennsylvania are launching new efforts to uncover how the development and maintenance of heart cells is influenced by DNA. These insights could help drive future research on new therapies for cardiac disease.
Penn Medicine researchers propose that nuclear architecture, which governs the availability of hundreds of genes within a cell, plays a critical role in achieving the proper identity of a cell. Specifically, they plan to study how the packaging and organization of DNA in 3D—meaning understanding how DNA folds and twists in a complex way to fit into the tiny space of a cell nucleus—impacts cell development. The work is supported by their previous research, which shows that nuclear architecture governs cardiac cellular identity during both development and disease.
“This research has the potential to significantly advance our understanding of how cardiac cells arise and keep their identity for a lifetime,” said Principal Investigator Rajan Jain, MD, an assistant professor of Medicine and Cell and Developmental Biology in the Perelman School of Medicine at the University of Pennsylvania. “By viewing congenital heart disease and other cardiac diseases through the lens of how DNA is organized in the cell, many therapeutic opportunities that have remained untapped may come to light.”
The way the nucleus is organized inside cells plays a crucial role in controlling the genes that determine cell identity. The nucleus acts like the command center of the cell, controlling what genes are accessible or available for use.
The Jain lab’s work suggests that the way the DNA is folded and arranged within the nucleus can determine which genes are accessible and active, influencing the cell’s identity. The way the DNA is folded and organized can be compared to a complex origami structure, where each fold and crease determines the final shape and function. The research aims to unravel the role of genome folding in controlling cell behavior, particularly in heart cells, and to identify key processes involved in this regulation. Researchers will also explore how the spatial positioning of DNA affects gene activity during the development of heart cells. By studying this process, researchers can examine how the identity of heart cells is maintained. This process is important for our overall health; incorrect development of heart cells or altering its identity could contribute to congenital heart disease or cardiomyopathy.
“As I trained it was always assumed that therapies can’t target specific proteins in the nucleus, but that has changed over the last few years,” Jain said. “Leveraging those advancements and past work as an inspiration, I hope this research will eventually allow us to design new medicines that will directly target how DNA is organized.”
This research is supported by the National Heart, Lung, and Blood Institute of the NIH (R35HL166663).
We are thrilled to celebrate the promotion of Core Member Liz Heller, Ph.D. to Associate Professor of Pharmacology. Please join us in congratulating Dr. Heller on this great achievement! We are excited to watch as your career continues to grow!
To learn more about Dr. Heller, please visit her lab website: https://hosting.med.upenn.edu/hellerlab/.
We are thrilled to celebrate the promotion of Core Member R. Babak Faryabi, Ph.D. to Associate Professor of Pathology and Laboratory Medicine. Please join us in congratulating Dr. Faryabi on this wonderful news and richly deserved achievement!
To learn more about Dr. Faryabi, please visit his lab website: https://faryabilab.com/.