Brian Black
A team of UCSF researchers has for the first time identified a genomic regulatory mechanism behind the formation of the cells that line the interior of blood vessels.
Their findings, published in the Dec. 12, 2008, issue of
Cell, not only advance the study of the human genome, but also could someday influence therapeutic treatments for cancer and other diseases linked to abnormal blood vessel growth, said Brian Black, PhD, the paper’s senior author and a professor and investigator at UCSF’s Cardiovascular Research Institute.
Black and his fellow researchers found that the development of endothelial cells is governed by two proteins working in tandem: FoxC2, from the forkhead protein family, and Etv2, from the Ets protein family.
Those proteins, also known as transcription factors, bind simultaneously to a single, composite sequence of DNA adjacent to the endothelial genes they regulate.
That discovery opens up a new window into the human genome, as it allows scientists to identify the locations of endothelial genes simply by seeking out that particular DNA sequence, Black said.
“This helps us understand the rules of the genome,” he said of his team’s findings. “If we understood other coding mechanisms in this way, we could identify other types of genes.”
The UCSF study also has significant implications for the treatment of diseases that involve aberrant blood vessel growth. Those include age-related macular degeneration, a condition that can lead to blindness, and the growth and spread of cancerous tumors, which are fueled in part by the formation of new networks of blood vessels.
By understanding how to block the interaction between FoxC2 and Etv2 — and thereby block new vessel growth — it might be possible to stave off those and other conditions, Black said.
Energized by their groundbreaking findings, Black and his team plan to move forward “very aggressively,” he said. They will focus on three main areas of research:
- Trying to understand the biochemical and biophysical basis of the interactions between FoxC2, Etv2 and DNA;
- Formally testing the molecular strategy behind the kind of re-formation of new blood vessels that contributes to disease;
and
- Looking for additional factors beyond FoxC2 and Etv2 that help determine blood vessel subtypes, including arteries, veins and lymphatic vessels.
In addition to Black, the
Cell paper’s co-authors include Sarah De Val, PhD, Neil Chi, MD, PhD, Joshua Anderson, PhD, Ian Harris, MD, Melissa Ehlers, Pooja Agarwal, Shan-Mei Xu and Didier Stainier, PhD, all of the UCSF Cardiovascular Research Institute; Stryder Meadows and Paul Krieg of the Department of Molecular and Cellular Biology at the University of Arizona; and Simon Minovitsky, Axel Visel, Len Pennacchio and Inna Dubchak of the Lawrence Berkeley National Laboratory’s Genomics Division.
Combinatorial Regulation of Endothelial Gene Expression
by Ets and Forkhead Transcription Factors
Sarah De Val, Neil C. Chi, Stryder M. Meadows, Simon Minovitsky,
Joshua P. Anderson, Ian S. Harris, Melissa L. Ehlers, Pooja Agarwal,
Axel Visel, Shan-Mei Xu, Len A. Pennacchio, Inna Dubchak,
Paul A. Krieg, Didier Y.R. Stainier and Brian L. Black
Cell (Dec. 12, 2008) 135(6):1053-1064
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