While every one of our cells contains all of our genetic information, each type of cell uses only specific parts of that information to make its proteins. Uncovering more about the mechanism that directs which particular pieces of genetic information the cell uses is the research focus of Mary Ann Osley, PhD, University of New Mexico Professor of Molecular Genetics and Microbiology and Co-Leader of the Cancer Biology and Biotechnology Program at the UNM Cancer Center. An understanding of this mechanism could help to understand how cancer arises-and therefore how we may be able to prevent it or treat it with specifically targeted drugs. Dr. Osley recently won a 4-year grant renewal to continue the epigenetic research she's been conducting for the past 22 years.
Epigenetics is the study of how the cell determines which part of the genetic information encoded in the DNA to act on. A long and extremely fine threadlike molecule, DNA loops and coils on itself in order to fit inside the cell nucleus. Proteins called histones attach to DNA to help in this looping and coiling process. Other molecules called histone modifications attach to the histones and, among other functions, control which parts of the DNA the cell is able to copy for protein synthesis. In cancer, histone modifications can activate cancer-causing oncogenes or repress tumor-suppressing genes; they can defeat the cell's built-in defenses against cancer. How and why these histone modifications behave this way is a key question Dr. Osley is trying to answer.
One area of her research has led to the discovery of a histone modification in which a small protein called ubiquitin attaches to a histone called H2B. Aptly named because it is found in almost every cell, ubiquitin performs many different functions. Dr. Osley's research has shown that when ubiquitin attaches to H2B one of its functions is to aid transcription, the first step in making a protein. Dr. Osley's research team first observed this H2B-ubiquitin behavior in yeast and other researchers have since seen the same behavior in mammalian cells. Dr. Osley's research is now focusing on how ubiquitin attaches to H2B and whether its presence or absence affects the cell's ability to copy DNA. Since many cancer cells have aberrant chromosomes, understanding where and how this DNA copying mechanism goes awry could lead to novel ways to target cancer cells.
Another area of Dr. Osley's epigenetic research has led to the study of quiescent cells. Although still alive, the transcription and DNA replication activity of quiescent cells is at a standstill. But almost immediately after giving them food, quiescent cells resume their activity. As Dr. Osley explains, "they rapidly start to grow again and we notice bursts of RNA being made as transcription takes place." Dr. Osley is studying many different histone modifications to try to understand how cells become quiescent and how they survive in this state. This research, she thinks, could lead to a completely new way to target cancerous adult stem cells.
Adult stem cells, which are different from embryonic stem cells, are the cells in our bodies that can rapidly renew our tissues by forming specific types of tissue. For example, adult stem cells in bone marrow can grow red or white blood cells but they can't grow brain cells. Adult stem cells are few in number and quiescent. That means that most cancer drugs don't affect them because cancer drugs target active cells, those cells that are in the process of dividing. So, if an adult stem cell is cancerous and quiescent, it can escape the effects of cancer drugs and survive to produce recurrent tumors.
"We think these histone modifications poise the genes to be in a ready state," Dr. Osley explains, "so quiescent cells can recognize when to turn on." Understanding what this ready state looks like-and how and whether it differs between cancerous and non-cancerous adult stem cells-will take some time. But the results could be well worth waiting for.
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