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Maintaining fences in the genetic landscape

Human Biology Division discovery reveals that the CTCF protein that forms protective boundaries between inactive, active sets of genes; may shed light on how some cancers develop
 Dr. Galina Filippova and James Moore
Co-authors Dr. Galina Filippova and James Moore, research technician, analyze the newly identified CTCF-binding site at the boundary between domains of active and inactive genes on the X chromosome. Photo by Todd McNaught

Just as fences and property lines help prevent a landowner from encroaching on another's turf, boundaries between sets of genes on our chromosomes are crucial for maintaining order in the genome. Without such genetic lines in the sand, chromosomes turn into lawless societies where genes switch on or off with abandon, sometimes leading to disease or developmental defects.

"Without boundaries between different regions of chromosomes, it's like a society without any rules," said Dr. Galina Filippova, a staff scientist in the Human Biology Division. "Organization is very important for making sure that genes are turned on or silenced at the proper time."

Architect of organization

In a paper published in the January issue of Developmental Cell, Filippova and colleagues at the University of Washington and Children's Hospital and Regional Medical Center report the discovery of what appears to be one of the key architects of this vital organization. They have found that a protein called CTCF, which has virtually identical forms in humans and mice, produces a protective boundary between inactive and active sets of genes on chromosomes. The work is the first to show that CTCF can form boundaries that protect entire chromosomal domains. Previous studies of the protein had demonstrated that it could shield a single gene from inappropriate control of its activity. The authors show that while CTCF isn't the protein that draws the property lines between active and silenced domains, it is absolutely essential for keeping the fence between them intact.

Understanding how CTCF controls gene activity is important because abnormal levels or forms of the protein have been implicated in some cancers. For example, small mutations in CTCF that alter, but don't abolish, its function have been found in human breast, kidney and prostate tumors. In addition, the CTCF gene "lives" in a part of the genome that is sometimes missing or damaged in certain cancers, leading researchers to suspect that one of CTCF's normal roles is to protect cells from becoming cancerous.

Finding CTCF

To study CTCF function, Filippova and colleagues examined one of biology's classic examples of a chromosome on which boundaries are critical — one of the two X chromosomes in female mammals. In humans, mice and other mammals, female cells contain two X chromosomes. Because male mammals only have one X chromosome, female cells inactivate one of their two X chromosomes to ensure that males and females have an equal number of active X-chromosome genes. However, a small number of the genes on the inactivated X must stay active or the female develops abnormally, as is the case with women who have Turner syndrome. Turner syndrome occurs when women are born with only a single X chromosome and typically causes infertility and multiple other medical abnormalities.

The researchers found that the CTCF protein was located at the boundary area between domains of inactive and active genes on the mouse X chromosome and report similar findings for the human X chromosome.

CTCF is known to bind to numerous sites throughout the genome, said Filippova, who was the first to clone, or isolate, the CTCF gene in fruit flies, mice and humans while she was a postdoc in Dr. Steve Collins' lab. The researchers expect that CTCF plays the same boundary role on other chromosomes that have distinct domains of activity and inactivity. More recently, Filippova and colleagues found that the fruit-fly version of CTCF also plays a boundary function, demonstrating the importance of this protein across a wide range of species.

Smart protein

"What is remarkable is how the protein knows where to bind since these sites all look different," she said. "In virtually every binding site that has been studied, CTCF recognizes a different sequence of DNA. We'd like to understand why and how a protein so similar among species binds to such different sequences. We also would like to understand when either the site is changed or the protein is mutated, why this may lead to cancer."

In conjunction with Dr. Chris Kemp's lab, she has found that mice that lack CTCF do not survive, and those missing a single copy are predisposed to multiple forms of cancer that in many cases mimic the same forms of the human disease.

Co-authors of the paper included James Moore and Ying Hu, research technicians working with Filippova; Dr. Christine Disteche and lab members Dr. Mimi Cheng and Jean-Pierre Truong, of the University of Washington; and Dr. Karen Tsuchiya, of Children's Hospital and Regional Medical Center.

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