Pioneers in Epigenetics Awarded Horwitz Prize

NEW YORK, NY (September 6, 2016)—Columbia University will award the 2016 Louisa Gross Horwitz Prize to Howard Cedar, PhD, and Aharon Razin, PhD, of the Hebrew University of Jerusalem, and Gary Felsenfeld, PhD, of the National Institutes of Health, for their fundamental work on how molecules can regulate the structure, behavior, and activity of DNA without modifying its genetic code. Their research, which has yielded key insights into how cells and embryos develop, led to the formation of the field of biology called epigenetics.

The Horwitz Prize, first awarded in 1967, is Columbia University’s top honor for achievement in biological and biochemical research. Forty-three Horwitz Prize awardees have gone on to win Nobel Prizes.

“These three scientists have advanced our understanding of how gene regulation works and what happens when the processes go wrong,” said Lee Goldman, MD, Harold and Margaret Hatch Professor of the University, dean of the Faculties of Health Sciences and Medicine, and chief executive of Columbia University Medical Center. “These are fundamental medical discoveries that may lead to innovative treatments for a range of diseases.”

“These researchers laid the foundation for an important new field of study,” said Gerard Karsenty, MD, PhD, chair of the Horwitz Prize Committee and chair of the Department of Genetics and Development at Columbia University Medical Center. “As our cells divide and become more specialized they need instructions on which genes to use and which to ignore. Epigenetics adds these annotations to our biological textbook; it’s a process that is crucial to our development and continues throughout our lives.”

Dr. Cedar’s and Dr. Razin’s work has identified several key properties of an epigenetic process known as methylation, in which small chemical molecules, called methyl groups, are added to DNA. This alteration does not change the DNA’s genetic code but affects how and when genetic information is used.

In their early studies, the Hebrew University scientists demonstrated that cells inherit methylated DNA in a way similar to how genetic code is passed down: One strand is used as a template for copying the methylation pattern to the other.  Later, the Cedar and Razin labs investigated the influence of methylation on gene activity and performed several experiments that showed that adding methyl groups to DNA could switch genes off.

Research by the Cedar and Razin groups revealed a mechanism by which methylation could silence genes. Their work demonstrated that highly methylated DNA could attract enzymes that wound DNA tightly around bead-like proteins called histones, effectively blocking access to that stretch of DNA.

To understand the role of methylation in development, Dr. Cedar and Dr. Razin investigated what happens inside a mouse embryo and found that nearly all methylation marks were erased early on in development, and a new profile established. This work gave rise to the concept of epigenetic reprogramming, a key process in development that erases and re-establishes the ability of cells to transform into different types.

Dr. Felsenfeld’s research has helped demonstrate how the structure and organization of chromatin, the complex of DNA and proteins in the nucleus, can regulate gene expression and give each kind of cell its characteristic properties.

Some of Dr. Felsenfeld’s early work focused on understanding how genes could be switched on when covered in proteins called histones, which wind the DNA into tighter structures. He showed that a “regulatory” region of DNA remained free of histones, leaving room for proteins that modulate gene activity. He also explored the role of the individual histone proteins in organizing chromatin structure.

Dr. Felsenfeld’s interest in the control of gene expression led him to study a stretch of genes that make hemoglobin, an oxygen-transporting protein found in blood cells.  After identifying proteins that regulate the activity of these genes, his team investigated a “boundary” sequence of DNA that blocks the globin genes from communicating with their neighbors.

This work led to the discovery that a protein present in the boundary, CTCF, prevents two regulatory regions from interacting when it binds to a DNA site that lies between them. Dr. Felsenfeld’s team showed that this property, called “insulation,” helps the cell produce the right amount of the growth hormone Igf-2. CTCF silences one copy of the Igf-2 gene, while the other copy is methylated, keeping CTCF away and the gene switched on. This phenomenon, known as “imprinting,” occurs in a “parent-of-origin” manner, in which the gene is expressed or silenced according to the sex of the parent from whom it is inherited; imprinting plays an important role in development.

Based on Dr. Felsenfeld’s studies of the properties of CTCF, subsequent work by many groups has shown that CTCF rearranges DNA into large “loop” structures. These loops organize the genome into separate neighborhoods, in which elements within a neighborhood “talk” to one another, but there is little talk between neighborhoods.

“The work of this trio is an excellent demonstration of just what’s needed to make a lasting breakthrough in science,” said Michael Purdy, PhD, executive vice president for research at Columbia University. “To uncover new processes, they had to continually develop new tools and work with new systems. This innovative spirit—in the service of scientific astuteness—is why they are worthy winners of the 2016 Horwitz Prize.”

Awardee Biographies

Howard Cedar, MD, PhD, is an emeritus professor of molecular biology and the Edmond J. Safra Distinguished Professor (Emeritus) at the Hebrew University of Jerusalem's Faculty of Medicine. He received his BSc from the Massachusetts Institute of Technology and his MD and PhD in medical science from New York University.

Aharon Razin, PhD, is an emeritus professor of biochemistry and the Dr. Jacob Grunbaum Chair of Medical Science (Emeritus) at the Hebrew University of Jerusalem's Faculty of Medicine. He received his BSc, MSc, and PhD in biochemistry from the Hebrew University of Jerusalem.

Together, Dr. Cedar and Dr. Razin have been honored both in Israel and internationally for their work on DNA methylation, with numerous awards and election to prestigious scientific associations, including the European Molecular Biology Organization and the Israel Academy of Sciences and Humanities. They have published more than 150 papers each in peer-reviewed journals and collaborated on more than 30 articles.

Gary Felsenfeld, PhD, is a senior investigator of the Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and an NIH Distinguished Investigator. He received his BA from Harvard University and his PhD from the California Institute of Technology.

Dr. Felsenfeld has won numerous international awards in molecular biology, and is an elected fellow of the American Association for the Advancement of Science, and the American Academy of Arts and Sciences, and a member of the National Academy of Sciences. He has authored more than 200 papers in peer-reviewed publications.

The Louisa Gross Horwitz Prize

The Louisa Gross Horwitz Prize was established under the will of the late S. Gross Horwitz through a bequest to Columbia University. It is named in honor of the donor’s mother, Louisa Gross Horwitz, who was the daughter of Dr. Samuel David Gross (1805–89), a prominent Philadelphia surgeon who served as president of the American Medical Association and wrote Systems of Surgery. Of the 94 Horwitz Prize winners to date, 43 have gone on to receive Nobel Prizes. Most recently, the 2013 Horwitz Prize winners, Edvard I. Moser, PhD, and May-Britt Moser, PhD, of the Norwegian University of Science and Technology in Norway, and John Michael O’Keefe, PhD, of University College London, shared the 2014 Nobel Prize in Physiology or Medicine. For a list of previous Horwitz Prize awardees, please click here.

The 2016 Louisa Gross Horwitz Prize Lectures will be held on Tuesday, November 22, 2016, followed by an awards ceremony.

Howard Cedar, MD, PhD, will present his lecture, “The Secret of DNA Methylation,” at 10:00 a.m. in Davis Auditorium (Rm. 412), Schapiro Center (CEPSR), 530 West 120 Street, on Columbia University’s Morningside Campus.

Gary Felsenfeld, PhD, will present his lecture, “Chromatin Structure, Epigenetic Mechanisms, and Long-Range Interactions in the Nucleus,” at 3:30 p.m. in the Clyde and Helen Wu Auditorium, Roy and Diana Vagelos Education Center, 104 Haven Avenue, at Columbia University Medical Center.

For more information about the Louisa Gross Horwitz Prize and the November lectures, please visit http://www.cumc.columbia.edu/research/horwitz-prize.