For their fundamental work on how molecules can regulate the structure, behavior and activity of DNA without modifying its genetic code, Columbia University will in November award the 2016 Louisa Gross Horwitz Prize to Hebrew University epigenetics and cancer researchers Prof. Howard Cedar and Prof. Aharon Razin – along with Prof. Gary Felsenfeld of the US National Institutes of Health.
Their research, which has produced 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. So far, 43 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 Prof. Lee Goldman, 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 Dr. Gerard Karsenty, chairman of the Horwitz prize committee and of Columbia Medical Center’s genetics and development department. “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.”
Cedar is an emeritus professor of molecular biology and the Edmond J. Safra Distinguished Professor (Emeritus), at Hebrew U’s Faculty of Medicine.
He received his bachelor’s of science from the Massachusetts Institute of Technology and his MD and PhD in medical science from New York University.
Razin is an emeritus professor of biochemistry, and the Dr. Jacob Grunbaum Chair of Medical Science (Emeritus), at the Faculty of Medicine.
He received his BSc, MSc and PhD in biochemistry from the Hebrew University.
The Israeli researchers’ 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, they 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, Cedar and 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 reestablishes the ability of cells to transform into different types.
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 his 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.
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, called CTCF, prevents two regulatory regions from interacting when it binds to a DNA site that lies between them. 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.
“The work of this trio is an excellent demonstration of just what’s needed to make a lasting breakthrough in science,” said Dr. Michael Purdy, Columbia University’s executive vice president for research. “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.”