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Bioinformatics researchers from UC San Diego just moved closer to
unlocking the mystery of how human cells switch from "proliferation
mode" to "specialization mode." This computational biology work from
the Jacobs School of Engineering's bioengineering department could lead
to new ideas for curbing unwanted cell proliferation—including some
This research, published in Nature Genetics, could also improve our
understanding of how organs and other complex tissues develop.
The UC San Diego bioengineers are part of a Japan-based global
research consortium, the Genome Network Project, which generated one of
the first close-to-comprehensive looks at a human cell's entire network
of proteins called "transcription factors." Each human cell contains
approximately 2,000 transcription factors, which are proteins that bind
to specific locations on the cell's DNA. Once bound to DNA,
transcription factors work to either encourage or prevent
"transcription"—the process by which messenger RNA is generated from
DNA. These messenger RNA strands then travel to cellular factories
called ribosomes which churn out proteins based on the specifications
of the mRNA.
"Transcription is one of the most important events in the cell…it
determines cell morphology and cell function," said Timothy Ravasi, a
UC San Diego research scientist from the bioengineering department and
author on the new Nature Genetics paper.
Researchers have long understood that most transcription factors in
human cells do not work alone, but studying the entire network of
transcription factors within a cell has been difficult until now. In
the new study, the researchers used a series of computational and
integrative biology approaches in order to look at how the activity of
the network of transcription factors in a myeloid leukemia cell line
changes over time.
"Leukemia" refers to a variety of pathologies involving uncontrolled
proliferation of white blood cells. Understanding the role of the
transcriptional network during differentiation in leukemia cells could
offer a glimpse into the cause of leukemia, or offer possible
approaches for treating leukemia, according to Ravasi.
During the laboratory phase of the project, researchers introduced a
compound that stopped cell proliferation in the myeloid leukemia cell
line. Next, they collected as much information as possible regarding
the activity of the transcription factor network during the processes
of differentiation and maturation into immune cells known as monocytes
and macrophages. Computational work performed at UC San Diego after all
the laboratory data had been collected allowed the researchers to
identify specific subnetworks of transcription factors that were
activated at particular time points.
The UCSD researchers were challenged to integrate different but
related data sets in order to tease out real signals from noise. This
is known as "integrative biology."
"We take lots of measurements of the same thing…we integrate them
together," which leads to higher confidence in experimental results,
Ravasi explained. Measuring both messenger RNA and protein levels, is
one example. Detection of both signals provides two independent data
points indicating the presence of the same protein.
"Getting to be the first to analyze and make sense of this large and
fascinating data set was a huge opportunity," said Ravasi. The UC San
Diego bioinformatics team working on this project included Ravasi and
two post-doctoral researchers from Trey Ideker's bioengineering
laboratory, Ariel Schwartz, now at Synthetic Genomics, and Kai Tan, now
an assistant professor of internal medicine and biomedical engineering
at the University of Iowa.
By monitoring the activity of the transcriptional network one hour
after the onset of differentiation, the researchers identified a gene
that appears to play an important role in cell differentiation in white
blood cells. "It's a long shot, but if you found a compound that
inhibits this gene, you could make the cells begin to differentiate
towards a normal monoblast line rather than continue unchecked cell
proliferation," said Ravasi.
Resilient and Redundant
Based on the new research, it appears that the network of
transcription factors from the human myeloid leukemia cell line is
redundant and resilient, explained Ravasi.
The researchers turned-off or "knocked down" 52 transcription
factors, one at a time, in order to study their individual role within
the network. Most of the single knock-downs did not result in changes
to cell differentiation or cell shape.
"The transcriptional network for this cell type appears quite
redundant which likely makes the network resilient to mutations or
environmental agents that could interfere with transcription factor
function," said Ravasi. "My guess is that we will find similar
redundancy in the transcription networks of other cell lines, and in
the transcription networks that regulate other aspects of cell
function, but we can't say that from these data."
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