Michael Grunstein photo

Penn Epigenetics Institute Mourns the Loss of Michael Grunstein, PhD

The Epigenetics Institute mourns the loss of Michael Grunstein, PhD, whose work is foundational to the study of chromatin and epigenetics. In addition to his groundbreaking scientific discoveries in the 1990’s revealing the central biological role of histones and their acetylation modifications, Michael was also a treasured colleague who challenged those around him in a positive way to advance the field.  My own early research in the transcription and chromatin field was deeply affected by long, memorable, and heated discussions with Michael at many conferences.  Below please find an announcement of Michael’s passing written by Siavash Kurdistani, MD, who was a post-doc and colleague to Michael. Please read Siavash’s wonderful memorial to Michael’s inspiring life and work.

Shelley

Shelley L. Berger, PhD
Director, Penn Epigenetics Institute


Michael Grunstein, PhD
In Memoriam
February 18, 2024

It is with profound sorrow that I share the news of the passing of Michael Grunstein, a distinguished professor, valued colleague and pioneering scientist in the field of chromatin and epigenetics. After a nearly 20-year battle, he succumbed to complications from Parkinson’s disease early this morning, with his family by his side at home. This loss is particularly personal to me as Michael was not only my postdoctoral advisor but also instrumental in helping me establish my independent career at UCLA.

Scientific breakthroughs are narratives of individuals and their journeys. Michael’s story is a prime example of this, illustrating the human elements that drive scientific discovery.

Michael was born in Romania in 1946 into a family of Holocaust survivors. After immigrating to Canada, he built a strong foundation in scientific fundamentals with a B.Sc. in Genetics and Chemistry from McGill University in 1967. He earned his Ph.D. at the University of Edinburgh’s Institute of Animal Genetics, working with Dr. Max Birnstiel in a lab recognized for isolating the first gene (rDNA). Michael then moved to Stanford for postdoctoral research, first with Dr. Larry Kedes in the Department of Medicine where he applied insights from rDNA to investigations of histone mRNA, and later with Dr. David Hogness in the Department of Biochemistry. It was in the Hogness lab that Michael developed colony hybridization, a powerful method that revolutionized gene mapping and chromosome isolation from complex mixtures. The technique, known as a “Grunstein,” was a mainstay of molecular biology research for more than two decades.

Upon joining UCLA in July 1975, Michael chose to study histones, driven by his intrigue with DNA packaging proteins and a deliberate choice to steer clear of what he perceived as the crowded field of transcription regulation research. Initially working with sea urchins, a chance confluence of events, including the destruction of the sea urchin population in the Gulf of California by Hurricane Liza in 1976, prompted him to switch to budding yeast as his model organism. This decision was further catalyzed by the development of a method to transform yeast cells, a breakthrough achieved by Gerald Fink and colleagues in 1978.

Utilizing yeast genetics, the Grunstein lab established that histones were not merely packaging proteins for DNA but contribute to regulation of gene expression. A key breakthrough was the demonstration that histones cooperate with the yeast SIR proteins to establish heterochromatin, a first such model for how specialized domains of chromosomes can be formed. His pioneering discoveries opened a novel field of inquiry and laid the foundation for the study of epigenetics in biology and disease.

Reflecting on Michael’s journey, we can discern the key attributes that lead to scientific breakthroughs. Curiosity led him to find fascination in what many considered mundane—packaging proteins. Creativity guided him to explore questions overlooked by others. Courage was evident in his consequential pivot from sea urchins to a then-emerging model organism—the budding yeast. Willingness to follow nature and experimental results allowed him to perceive that packaging proteins play important roles in gene regulation. Resolve and luck, enabled him to make the best of what was available to him, culminating in seminal contributions to science.

Michael received widespread acclaim for his groundbreaking work, earning him national recognition and his election to the American Academy of Arts and Sciences and the National Academy of Sciences. Among his many awards were the Lasker Basic Medical Research Award, the Albany Prize, the Gruber Genetics Prize and the Massry Prize. He shared these honors with C. David Allis, who credited Michael’s influential work in the 1980s as the inspiration for his own entry into the field of epigenetics.

Michael’s success, like that of many scientists, was made possible by the contributions of a talented group of student and postdoctoral trainees. Additionally, he was fortunate to have the tireless support of his spouse, Dr. Judith (Judy) Grunstein. Judy played a crucial role both within and outside the laboratory setting. She helped Michael establish his laboratory at UCLA and made significant contributions to his research. One notable contribution was an important early paper that characterized the sea urchin histone H4 gene. Later, Judy earned a dentistry degree from UCLA and dedicated over three decades to practicing in the community.

Michael served as Chair of the Department from 2007 to 2010 and retired from UCLA on June 29, 2016.

Beyond his scientific endeavors, Michael had a passionate interest in gardening. He approached gardening not just as a leisure activity but with serious dedication. At its peak, his garden was yielding an impressive 3 tons of avocados annually, in addition to a bountiful variety of other fruits and vegetables.

Michael leaves behind his loving wife Judy, their daughter Davina, their son Jeremy and daughter-in law Elisa, and four grandchildren: Jasper, Rowan, Emilia and Josie. Our thoughts are with the Grunstein family during this immensely difficult time, and we offer them our deepest sympathies and support.

I invite you to listen to Michael’s Lasker speech in which he describes his contributions to science and offers personal reflections on his career:  https://vimeo.com/291819942.

In honor of Professor Grunstein’s inspiring legacy and enduring contributions to the Department,

Siavash

Siavash K. Kurdistani, MD
Professor and Chair
Department of Biological Chemistry
David Geffen School of Medicine at UCLA

Marisa Bartolomei, PhD, Awarded the 2024 March of Dimes Richard B. Johnston, Jr., MD Prize

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.

Arjun Raj, PhD, Awarded George H. Heilmeier Faculty Award for Excellence in Research

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.

Click here for more information.

Rexxi Prasasya Headshot, Congratulations Graphic

Congratulations Rexxi Prasasya, PhD, K99 Pathway to Independence Award Recipient

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.

Congratulations Yanxiang Deng!

Congratulations Yanxiang Deng, 2023 Blavatnik Regional Award Laureate!

Congratulations to Yanxiang Deng, PhD, who has been awarded the 2023 Blavatnik Regional Award for Young Scientists in the Life Science category.

Dr. Deng was recognized for developing a novel microfluidic method for “spatial-omics” to profile expression of RNA, proteins, and epigenetic markers across spatially organized groups of cells in tissues. Deng’s work has allowed us to construct a map of how RNA, proteins, and epigenetic markers are expressed across groups of cells with respect to cells’ relative positions. This work provides critical insight about how cells in different regions change their behavior during processes like development and disease.

The Blavatnik Regional Awards acknowledge and celebrate the excellence of outstanding postdoctoral scientists from institutions in New York, New Jersey, and Connecticut working in the three disciplinary categories of Life Sciences, Physical Sciences & Engineering, and Chemistry.

Click here to learn more about the Blavatnik Awards.

Click here to visit the Deng Lab website.

Award Announcement Graphic

Congratulations to our 2024 Epigenetics Institute At-Large Pilot Grant Awardees!

The Penn Epigenetics Institute is pleased to announce the awardees of the 2024 At-Large Pilot Grants. Since 2013, these pilot grants have supported new research projects across a broad spectrum of topics, from those that involve fundamental studies in epigenetics to more applied or disease-oriented studies that utilize epigenetics as a central component of the research. We were grateful to receive a number of high-quality applications this year, and we are looking forward to seeing the results of the funded projects.

New Awards:

Liling Wan, PhD & Eric Joyce, PhD: “Drugging oncogenic condensates using high-throughput chemical and imagine screens”

Yanxiang Deng, PhD: “Spatial Epigenome Sequencing at Tissue Scale and Cellular Level”

Renewal Awards:

George Burslem, PhD & Andrey Poleshko, PhD: “Unbiased Probe Discovery for Epigenetics Reprogramming”

Erica Korb, PhD & George Burslem, PhD: “Developing tools to examine the role and regulation of histone crotonylation in the brain”

New, precise, and efficient DNA sequencing method may lead to easier testing and earlier cancer detection

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.

——————————————-

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).

Discovering Cell Identity: $6 Million NIH Grant Funds New Penn Medicine Research to Uncover Cardiac Cell Development

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.

————————————————————-

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).

 

 

Previous Next
Close
Test Caption
Test Description goes like this