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National Ataxia Foundation - National Ataxia Foundation Research
William G. Fairbrother, Ph.D.
NAF Research 2014
William G. Fairbrother, Ph.D.
Brown University, Providence, RI
Technology - Genetic Variation and RNA binding proteins: tools and techniques to detect functional polymorphisms (Case 2251)
William Fairbrother, PhD, Associate Professor of Biology
Department of Bio Med Molecular, Cellular Biology Biochemistry
Using a technology he ...
Using a technology he invented, Brown researcher William Fairbrother (pictured center) and colleagues have discovered new molecular interactions in the process that will help regenerative medicine researchers better understand pluripotency.
In a study, Fairbrother's
team showed that different proteins called transcription factors compete and cooperate in the cells to produce complex bindings along crucial sequences of DNA.
This game of molecular "capture the flag," played in teams and amid shifting alliances, appears to be a necessary part of what determines whether stem cells retain their pluripotency and whether specialized, or differentiated, cells can regain it.
In recent years scientists have reported spectacular successes in turning fully differentiated cells back into pluripotent stem cells, a process called reprogramming.
But the animals derived from these cells often suffer higher rates of tumors and other problems, Fairbrother
The reason may be because the complex details of the reprogramming process haven't been fully understood.
said there are many misconceptions about how reprogramming transcription factors interact with DNA.
"Most people think of a protein binding to DNA as a single, surgical thing where you have this isolated binding event," Fairbrother
"But in fact we show that sometimes these binding events occur over hundreds of nucleotides so they seem more like great greasy globs of proteins that are forming.
In addition, the proteins interact with each other, diversifying their function by appearing in complexes with different partners at different places."
By employing a high-throughput, high-resolution binding assay that he's
dubbed MEGAShift, Fairbrother
colleagues, who include pathology researchers from the University of Utah School of Medicine
, were able to analyze the interactions of several key transcription factors in a region of 316,000 letters of DNA with a resolution as low as 10 base pairs.
Through hundreds of thousands of array measurements, lead authors Luciana Ferraris (pictured left) and Allan Stewart, Fairbrother
, Alec DeSimone (pictured right), and the other authors learned of previously unspotted patterns of protein interactions.
"Who binds next to a protein is a determinant of who ends up binding to a sequence," Fairbrother
With support from the National Institutes of Health
group is also applying MEGAShift to other questions, including how protein-protein interactions affect the formation of RNA-protein complexes, which can be even more complicated than binding DNA.
"Something like 85 percent of the ...
"Something like 85 percent of the mutations in the Human Gene Mutation Database are presumed to affect how proteins are coded, but what this work shows is that 22 percent of those are affecting the splicing process," says William Fairbrother, assistant professor of biology at Brown University.
Add that to the 15 percent already believed to affect splicing of mRNA, and nearly one in three mutations in the HGMD may owe at least part of their harmful results-hundreds of hereditary diseases-to the way in which they cause splicing errors.
"Splicing mutations are already known to be a large fraction, but we're saying they are even more," Fairbrother
"A processing defect may be able to be detected and fixed much more easily and safely than a protein coding defect," Fairbrother
and the study's lead author, computer science graduate student Kian Huat Lim developed a new computer to analyze the human genome and data on splicing operations.
Bio-IT World | According to a ...
Bio-IT World | According to a paper published in the Proceedings of the National Academy of Sciences this week, nearly one third of the mutations listed in the Human Gene Mutation Database (HGMD) may be caused by splicing errors in mRNA. â€œSplicing mutations are already known to be a large fraction, but weâ€™re saying they are even more,â€ said William Fairbrother, assistant professor of biology at Brown University and senior author of the study.Â
6/12/2011 6:52:06 AM