Yong Cai, Ph.D., Research Specialist I, and Jingji Jin, Ph.D., Senior Research Associate, are the paper's coequal first authors.

The paper, YY1 Functions with INO80 to Activate Transcription, was posted to the Web site of Nature Structural & Molecular Biology on Aug. 26. It describes data showing that transcription factor YY1 works with a chromatin remodeling complex INO80.

The paper offers the first demonstration of several interesting principles, said Dr. Joan Conaway. We learned that there is a role of the INO80 complex in gene regulation; that a chromatin remodeling complex plays a role as a coactivator for YY1; and that a transcription factor may travel with the remodeling complex required for it to gain access to promoters ” suggesting that an initiating event in YY1-dependent gene activation is the corecruitment of YY1 and the human INO80 chromatin remodeling complex.

YY1 is known to be important for turning on and off a significant number of genes, including genes that control cell division, cell differentiation, and development. Because of these contributions to cell cycle control, YY1 may eventually prove to be a good target for cancer therapy ” but only if more can be learned about its functional mechanism.

One of the most interesting findings in this paper is that one way YY1 controls gene expression is to bring the INO80 chromatin remodeling complex to the DNA sequences that control when a gene is turned on or off, said Dr. Ron Conaway. This process can make the gene available, or not, to the machinery that copies DNA into messenger RNA, which in turn directs the cell to make proteins.

This research is important because it illustrates that YY1 represents a switch point for modifying the activity of genes, said Robb Krumlauf, Ph.D., Scientific Director. We know that YY1 plays a significant role in regulating cellular processes, but this work from the Conaway Lab skillfully addresses questions about its mechanism of action, and provides a wealth of new information about an important transcription factor.

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Another explanation “ that the mutations arise very early in the life of a germline cell and multiply through subsequent divisions “ also did not fit the data, Arnheim and Calabrese said.

But the clusters of mutant cells could be explained if the mutant cells made copies of themselves more frequently than normal cells.

If a mutant cell divided into two copies of itself every four to five years, the extra copies would be enough to explain the clusters, the researchers said.

They added that the model explains the increase in Apert risk with paternal age, while noting that other selection-based models also may be able to explain the same data.

Citing related studies along with their findings, the authors concluded that it now seems very likely that (natural) selection can be a driving force acting to increase the mutation frequency at a number of genes in humans.

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