Cells use mix-and-match approach to tailor regulation of genes

June 16, 2006

Scientists eager to help develop a new generation of pharmaceuticals are studying cellular proteins called transcription factors, which bind to upstream sequences of genes to turn the expression of those genes on or off. Some pharmaceutical companies are also hoping to develop drugs that selectively block the binding of transcription factors as a way to short-circuit the harmful effects of diseases, and researchers at the University of California, San Diego on June 16 reported new findings that could aid that effort.

Bioengineering researchers at UCSD and two research institutes in Germany report in the June 16 issue of PLoS Computational Biology that transcription factors act not only in isolation, but also in pairs, trios, and combinations of up to 13 to regulate distinct sets of genes. The researchers, led by UCSD bioengineering professor Trey Ideker, reported a list with 363 combinations of 91 central transcription factors that regulate a large proportion of genes in the yeast genome. The team used rigorous statistical tests to discover active combinations of transcription factors, as if the cells were mixing and matching parts of its regulatory-protein wardrobe to respond to different environmental conditions. The researchers expect that human cells use a similar system of transcription-factor combinations, but on a larger scale.

"A cell's surprising ability to mix and match so many different combinations of these factors to achieve a high degree of complexity and specificity in the expression of its genes is impossible for even the most experienced cell biologists to conceptualize," said Andreas Beyer, a post-doctoral fellow at the UCSD Jacobs School of Engineering's Department of Bioengineering. "That's why we have computers."

The researchers combined the results of their laboratory with other large-scale measurements of transcription factor-gene binding, such as those reported earlier by MIT biology professor Richard A. Young and his collaborators.

Ideker's team was able to identify new transcription factor binding patterns by borrowing a concept from computer science. The team considered the binding of one transcription factor to one gene as analogous to one "hop" of a data packet from one Internet router to another.

In the case of gene regulation, Ideker's team identified "2hop" relationships by first focusing on single transcription factor-gene associations, plus other experimental evidence that indicates that that gene regulates a second gene.

To enlarge the scope of the model further, Ideker's group also incorporated other previously discovered transcription-factor interactions and related genetic results. They relied on a total of eight types of direct and indirect evidence to create a model. That model predicts 980 as-yet-undiscovered transcription factor-gene binding interactions.

"This 'systems biology' approach, using so many different lines of evidence, has given us a much more revealing and detailed picture of how cells orchestrate gene regulation to cope with different environments," said Ideker. "We're far from understanding the full picture of gene regulation in a cell, but this new information should give scientists who are interested in blocking transcription factors a powerful new tool to narrow their search to the most promising candidates."
-end-
Other researchers involved in the project include: Christopher Workman, UCSD Jacobs School of Engineering's Department of Bioengineering (now at The Technical University of Denmark); Jens Hollunder and Thomas Wilhelm, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany; Dörte Radke and Ulrich Möller, Leibniz Institute for Natural Products Research and Infection Biology, Hans Knöll Institute, Jena, Germany.

Funding was provided by the National Institute of Environmental Health Sciences (NIEHS), the David and Lucille Packard Foundation, the German Academic Exchange Service, and the German Federal Ministry for Education and Research.

University of California - San Diego

Related Transcription Articles from Brightsurf:

Circular RNA regulates neuronal differentiation by scaffolding an inhibitory transcription complex
In a screening for a functional impact to the neuronal differentiation process, Danish researchers identified a specific circular RNA, circZNF827, which surprisingly 'taps the brake' on neurogenesis.

Transcription factors may inadvertently lock in DNA mistakes
A team of Duke researchers has found that transcription factors have a tendency to bind strongly to ''mismatched'' sections of DNA, i.e. sections of the genome that were not copied correctly.

New role assigned to a human protein in transcription and genome stability
DNA-RNA hybrids, or R loops, are structures that generate genomic instability, a common feature of tumor cells.

CeMM study reveals how a master regulator of gene transcription operates
Using TPD technology, CeMM researchers set out to understand set out to understand the primary role of a key regulator of transcription, the human Mediator complex.

Researchers find new role for dopamine in gene transcription and cell proliferation
A joint group of researchers at the George Washington University and the University of Pittsburgh have found that dopamine and the dopamine D2 receptor modulate expression via the Wnt/β-catenin signaling pathway.

SMAD2 and SMAD3, two almost identical transcription factors but with distinct roles
Both transcription factors regulate the expression of genes involved in embryo development, among other functions, although they exert very different roles.

Study explores role of mediator protein complex in transcription and gene expression
A new study led by Ryerson University called 'The Med31 Conserved Component of the Divergent Mediator Complex in Tetrahymena thermophila Participates in Developmental Regulation' advances existing knowledge about transcription and gene expression.

New members found in a transcription factor complex that maintains beta cells
A protein complex in the nucleus of beta cells contains different proteins that work together to regulate genes important for the development and maintenance of functional beta cells.

Testifying while black: A linguistic analysis of disparities in court transcription
A new study has found that court reporters transcribe speakers of African American English significantly below their required level of accuracy.

HKUST scientists discover how RNA PoII maintains accurate transcription with super computer
Scientists from the Hong Kong University of Science and Technology have recently uncovered the mechanisms of how RNA polymerase II performs intrinsic cleavage reaction to proofread RNA transcriptions, shedding light on how misregulation of accurate transcription can lead to diseases including cancer and Alzheimer's disease.

Read More: Transcription News and Transcription Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.