Matthew Guenther talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of Molecular
Biology & Genetics.
Article Title: A chromatin landmark and
transcription initiation at most promoters in human
MG;Levine, SS;Boyer, LA;Jaenisch, R;Young, RA
Year: JUL 13 2007
* Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA
* Whitehead Inst Biomed Res, Cambridge, MA 02142 USA.
* MIT, Dept Biol, Cambridge, MA 02139 USA.
Why do you think your paper is highly
This paper represents a shift in the way we think about regulation of gene
transcription. Our finding that the majority of human genes experience
transcriptional initiation runs contrary to previously held views that Pol
II recruitment is the rate-limiting or principle regulatory step in gene
transcription. This paper suggests that regulation of transcriptional
elongation is much more important to establishing cell-specific gene
expression programs than previously realized.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
We have discovered that most protein-coding genes, including most genes
thought to be transcriptionally inactive, experience transcriptional
initiation. Previous studies of a few genes, including the
Drosophila heat shock genes, have demonstrated that Polymerase II
molecules could be transcriptionally engaged at genes that were not
producing full-length mRNA.
"We now show that most human genes
have already begun the act of gene
These "paused" or "poised" polymerase molecules could produce a complete
mRNA transcript once an elongation block had been removed. This behavior
was thought to be a little-utilized exception rather than the general
transcriptional rule. We now show that this polymerase pausing, or a highly
similar mechanism, is utilized across the vast majority of human genes.
Would you summarize the significance of your paper
in layman's terms?
The proper control of gene transcription (which genes are turned on and
which genes are turned off at any given time) is critical to cell function
and development. Previously, it was thought that when a gene needed to be
turned on, an RNA Polymerase II molecule was recruited at that time to the
gene in order to produce a full-length gene transcript (the mark of an
We now show that most human genes have already begun the act of gene
transcription, even if they are indeed silent (turned off). This
"polymerase poising" indicates that many silent genes are already partially
turned on, but are waiting for further instructions that tell it to be
"fully turned on." Determining what these "further instructions" are, and
which proteins carry them out, will be of great importance in deciphering
how humans and other organisms develop properly.
How did you become involved in this research, and
were there any problems along the way?
We discovered the basis for this paper while mapping the gene regulatory
circuitry in embryonic stem cells and relating this information to
chromatin regulatory events (initially H3K4me3 modification). The initial
discovery was surprising and had to be verified in multiple ways using
Where do you see your research leading in the
The finding that transcriptional initiation occurs at most genes suggests
that regulation of transcriptional elongation is a central event in
determining cell-specific gene regulatory programs. As such, regulation of
development via transcriptional elongation control (by polymerase pausing
factors, elongation factors, kinases etc.) is likely to become a rich area
of exploration. Identifying these factors and how they act in a
gene-specific manner will be important in understanding human development
(including stem-cell biology and regenerative medicine) and disease (such
Matthew Guenther, Ph.D.
Whitehead Institute for Biomedical Research
Cambridge, MA, USA Web