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How major signaling pathways are wired to our genome gives new insight into disease processes
Date:10/27/2011

o the DNA adjacent to a master transcription factor, the main switch that turns the genes specific to each cell type on or off. In embryonic stem cells, SMAD3 nestles next to the master transcription factor Oct4.

"We were really surprised when we looked at the data because SMAD3 wasn't distributed with many different transcription factors. Instead, it appeared to be following Oct4, which is one of the transcription factors that determines embryonic stem cell state," says Mullen. "The master transcription factors are expressed at very high levels and dominate the transcription machinery because there is so much of these factors."

In muscle cells and specific immune system cells, Mullen saw similar results. SMAD3 only bound to the DNA next to the master transcription factors Myod1 and PU.1, respectively. Once associated with SMAD3, the master transcription factors adjust the nearby genes' expression.

Mullen's work indicates that a signal from one signaling pathway can interact with different master transcription factors in different cell types, which explains why the same signal can have distinct effects in multiple cell types. And the signal interacts with just one or a few master transcription factors in each cell typenot hundreds of transcription factors.

Related research from Young postdoctoral researcher Lee Lawton and graduate student Zi Peng Fan, who collaborated with the lab of Leonard Zon at Children's Hospital Boston, supports Mullen's findings. In an article in the same issue of Cell, the team's work with maturing blood cells shows that the BMP and Wnt signaling pathways use their respective signal molecules throughout the blood maturation process, but that the signals target various master transcription factors based on the cells' stage in this process.


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Contact: Nicole Giese
giese@wi.mit.edu
617-258-6851
Whitehead Institute for Biomedical Research
Source:Eurekalert

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