New faculty member Piroska Szabo, Ph.D., continues a 50-year City of Hope tradition of studying what is now called epigenetics.
Her work is defining how modification of DNA affects gene expression through the phenomenon of genomic “imprinting.” Most genes come in two copies — one inherited from the mother and the other from the father. Imprinting describes the process by which one of those genes in a pair can be inactivated.
Incorrect inactivation of many genes is seen in cancers. Anti-cancer genes known as tumor suppressor genes are often hypermethylated and thus silenced in tumor cells.
Szabo, who came to City of Hope in 1992 first as a postdoctoral fellow and then worked as a research scientist, was named assistant professor in the Division of Molecular Biology last year. She is particularly interested in how DNA modification by addition of methyl groups (DNA methylation) inactivates genes.
“The most interesting thing for me is how methylation differences are established between male and female germ cells,” Szabo said. “Methylation differences exist before fusion of sperm and egg into a zygote and are ‘remembered’ by cells through the course of life.”
Szabo studies a particular region of chromosomal DNA that regulates adjacent genes differently depending on whether they are inherited maternally or paternally. Before fertilization, that region – called the imprinting control region (ICR) – is methylated in sperm, inhibiting one of those genes, and not methylated in eggs, enabling expression of that gene.
One question that Szabo wants to answer is what happens when those methylation patterns are disturbed, because failure of a cell to keep track of which parent a member of a gene pair came from could lead to developmental abnormalities or cancer.
Epigenetic regulation in mammals was first identified at City of Hope with the work of Susumu Ohno, Ph.D., who in 1959 showed that in females an entire X chromosome, either the paternal or maternal one, is inactivated — in large part by methylation — so that females don’t make twice as many gene products from the X chromosome as do males (males have only one X chromosome, whereas females have two).
Ohno retired from City of Hope in 1996 but remained active in research until his death in 2000.
Szabo acknowledges indebtedness to scientists attracted here in part by Ohno’s pioneering work. “City of Hope is a very good environment because my colleagues here understand the importance of methylation,” she said. “The first person who proposed that DNA methylation has a role in gene regulation was Art Riggs.” Arthur Riggs, Ph.D., is now professor and director of Beckman Research Institute at City of Hope.
A five-year, $2.1 million grant from the National Institutes of Health will allow Szabo to analyze methylation changes caused by potentially harmful chemicals known as “endocrine disrupters.”
“These chemicals look and act like hormones but are man-made,” explained Szabo. “They are found in plastics, PVC tubes and even children’s toys.” One that she will focus on is vinclozolin, a fungicide associated with a decline in fertility. Szabo will examine methylation of the ICR in mouse germ cells after fetuses are exposed to endocrine disrupters.
“This project centers on environmental events that potentially affect our health because they change DNA methylation at important genomic regions,” said Szabo.
Szabo received her master’s degree in biology and her Ph.D. in molecular biology from the University of Szeged in Hungary. She is also co-director together with Walter Tsark, Ph.D., of City of Hope’s Transgenic Core.