NCI Scientists Visualize Gene Regulation
in Living Cells
A research team led by scientists at the National Cancer Institute
(NCI), part of the National Institutes of Health (NIH), has applied
advanced imaging methods and computer simulations to be able to
glance at the regulation of a cancer-related gene in a living cell.
They found that the efficiency with which the components of the
cellís gene reading machinery come together has an impact on gene
expression, the process by which a gene translates its information
into a new protein. The findings, published in the May 23, 2008
issue of Molecular Cell, shed new light on the means by
which living cells regulate gene activity.
ďEach new discovery in the realm of gene regulation gives us a
fuller appreciation of how a cell controls the expression of its
own genetic program,Ē said NCI Director John E. Niederhuber, M.D. ďThese
findings remind us that the puzzle is not yet complete, that there
are nuances to how genes are translated that we do not yet completely
A key question regarding how the cell controls gene expression
relates to interactions between genes and certain gene reading
proteins, and between genes and transcription factors, which regulate
gene transcription from DNA to RNA. The process requires the assembly
of numerous transcription complexes, particularly one called RNA
polymerase, at the site of a geneís promoter (the stretch of DNA
before the start of a gene to which transcription factors bind)
at the right time.
From earlier work done primarily by NCI researchers, the interactions
among transcription factors, and between them and their target
DNA, is known to be highly dynamic. What has remained unclear is
whether this dynamic nature itself serves some role in regulating
To understand the regulatory implications of this dynamism, a
team of scientists probed the relationships between a large gene-reading
complex known as RNA pol I and genes that encode ribosomal RNAs
(rRNAs), which are key components of the cellís protein manufacturing
machinery. The rRNA genes are excellent models for studying the
dynamics of regulation because their transcription factors are
well known, and their interactions with RNA pol I can be visualized
using quantitative live-cell fluorescent microscopy, a sophisticated
technique for analyzing the activities of proteins and genes in
living cells in real-time.
The groupís data suggest that there is indeed a regulatory role
for these dynamic relationships. RNA pol I is not a single protein
but rather a complex of subunits that assemble into the full polymerase
when needed. According to the researchersí observations, as the
cell increases rRNA production, some of the subunits associate
more stably with the gene and assemble active and complete RNA
pol I complexes more efficiently. As a result, the cellís production
of rRNA increases.
The scientists then interfered with the interactions between the
RNA pol I subunits and another transcription factor, thereby mimicking
the conditions of a cell that was able to produce rRNA at a high
rate. As a result, the efficiency of RNA pol I assembly and the
pace of rRNA output both decreased dramatically.
The findings suggest that the efficiency with which the RNA pol
I complex assembles all its subunits — which is controlled
by a dynamic interplay of polymerase and non-polymerase transcription
factors — plays a significant role in determining when a
given gene is turned on. While the group looked only at RNA polymerase
I, other research suggests that the phenomena they observed may
represent a general mechanism for regulating gene transcription.
The team that led this research included Tom Misteli, Ph.D., head
of the Cell Biology of Genomes Group within the Laboratory of Receptor
Biology and Gene Expression at NCIís Center for Cancer Research,
Stan Gorski, Ph.D., and Sara Snyder, Ph.D.
For more information on Dr. Misteliís laboratory, please go to http://ccr.nci.nih.gov/staff/staff.asp?profileid=5819.
For more information about cancer, please visit the NCI website
at http://www.cancer.gov, or
call NCIís Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Gorski SA, Snyder SK, John S, Grummt I, and Misteli T. Modulation
of RNA polymerase assembly dynamics in transcriptional regulation. Molecular
Cell, Volume 30, Issue 4, May 23, 2008.