Landmark study unlocks stem cell, DNA secrets to speed therapies

October 10, 2008
In mammalian nuclei, replication takes place at punctate sites or foci. Early-replicating foci localize to the interior of the nucleus (green), while the periphery of the nucleus and nucleoli harbor late replicating foci (red). Cytogenetic studies suggest very stable organization of the DNA within these labeled sites, but the molecular boundaries separating differentially replicating segments have remained elusive. High-resolution, microarray-based replication timing profiles (translucent graphs) revealed the sizes and locations of early- and late-replicating chromosome segments and demonstrated that they are highly conserved within a cell type, but globally re-organized and consolidated into larger coordinately replicating segments during differentiation of embryonic stem cells. Courtesy of Florida State University Department of Biological Sciences

In a groundbreaking study led by an eminent molecular biologist at Florida State University, researchers have discovered that as embryonic stem cells turn into different cell types, there are dramatic corresponding changes to the order in which DNA is replicated and reorganized.

The findings bridge a critical knowledge gap for stem cell biologists, enabling them to better understand the enormously complex process by which DNA is repackaged during differentiation -- when embryonic stem cells, jacks of all cellular trades, lose their anything-goes attitude and become masters of specialized functions.

As a result, scientists now are one significant step closer to the central goal of stem cell therapy, which is to successfully convert adult tissue back to an embryo-like state so that it can be used to regenerate or replace damaged tissue. Such therapies hold out hope of treatments or cures for cancer, Parkinson's disease, multiple sclerosis, spinal cord injuries and a host of other devastating disorders.

Using mouse and human embryonic stem cells, FSU researchers employed advanced imaging techniques and state-of-the-art genomics technology to demonstrate, with unprecedented resolution along long stretches of chromosomes, which sequences are replicated first, and which occur later in the process of differentiation.

"Understanding how replication works during embryonic stem cell differentiation gives us a molecular handle on how information is packaged in different types of cells in manners characteristic to each cell type," said David M. Gilbert, the study's principal investigator. "That handle will help us reverse the process in order to engineer different types of cells for use in disease therapies." Internationally renowned for his body of cutting-edge research on chromosomal structure and reproduction that he began as a doctoral student at Stanford University in the 1980's, Gilbert joined the FSU faculty and was appointed as the first J. Herbert Taylor Distinguished Professor of Molecular Biology in 2006.

Results from the FSU study, which includes contributions from researchers at three other institutions, are described in a paper published in the October 7, 2008, edition of PLoS Biology, a peer-reviewed journal that showcases biological science research of exceptional significance. So prodigious were the findings that the current paper -- "Global Reorganization of Replication Domains During Embryonic Stem Cell Differentiation" -- is focused solely on results observed in the mouse embryonic stems cells; data on the human cells will be detailed in a future report.

"We know that all the information (DNA) required to take on the identity of any tissue type is present in every cell, because we already can, albeit very inefficiently, create whole animals from adult

tissue through cloning," Gilbert said. "We also can make a kind of artificial embryonic stem cells, called induced pluripotent stem cells, out of many adult cell types, but there are two major hurdles remaining. First, the methods currently used rely on the unnatural retroviral insertion of genes into patients' cells, and these genes are capable of forming tumors. Second, this method is very inefficient as well because only one in 1,000 cells into which the genes are inserted becomes pluripotent. We must learn how cells lose pluripotency in the first place so we can do a better job of reversing the process without risks to patients.

"The challenge is, adult cells are highly specialized and over the course of their family history over many generations they've made decisions to be certain cell types rather than others," he said. "In doing so, they have tucked away the information they no longer need on how to become other cell types. Hence, all cells contain the same genetic information in their DNA, but during differentiation they package it with proteins into 'chromatin' in characteristic ways that define each cell type. The rules that determine how cells package DNA are complicated and have been difficult for scientists to decipher."

But, Gilbert noted, one time that the cell "shows its cards" is during DNA replication.

"During this process, which was the focus of our FSU research, it's not just the DNA that replicates," he said. "All the packaging must be replicated as well in each cell division cycle."

He explained that embryonic stem cells have many more, smaller "domains" of organization than differentiated cells, and it is during differentiation that they consolidate information.

"In fact, 'domain consolidation' is what we call the novel concept we discovered," he said.

Gilbert likened the concept of domain consolidation to the undeclared or "undifferentiated" college student who then consolidates her literature resources during the course of declaring a major and specialization. "From a student with books on all subjects on all of her bookshelves comes a student who has placed all texts pertaining to her major on the eye-level shelf and moved the distantly-related, potentially distracting texts to the hard-to-reach bottom or top shelves," he said.

"Now, our challenge as scientists," said Gilbert, "is to build on what we've learned about domain consolidation so that we can efficiently and safely create patient-specific induced pluripotent stem cells or even coax the body's cells to change their specialization in response to medications."

Source: Florida State University

Explore further: Role model stem cells: How immune cells can self-renew

Related Stories

Role model stem cells: How immune cells can self-renew

January 21, 2016

When our organs age or wear out, their renewal usually depends on a few stem cells in the tissue, because the vast majority of differentiated cells have lost their ability to divide and generate new cells. A German-French ...

How to detect and preserve human stem cells in the lab

January 22, 2016

Human stem cells that are capable of becoming any other kind of cell in the body have previously only been acquired and cultivated with difficulty. Scientists at the Max Delbrück Center for Molecular Medicine (MDC) in the ...

The beauty of butterflies

January 26, 2016

Butterflies' special place in human culture stems from the fact that they have used their wings not only for flight, but as a canvas for some of the most striking patterns in nature. Evolving from an ancestral moth-like insect ...

Researchers pinpoint place where cancer cells may begin

January 20, 2016

Cancer cells are normal cells that go awry by making bad developmental decisions during their lives. In a study involving the fruit fly equivalent of an oncogene implicated in many human leukemias, Northwestern University ...

Clarifying the mechanism for making blood cells

January 20, 2016

In 1917, Florence Sabin, the first female member of the US National Academy of Sciences, discovered hemangioblasts, the common precursor cells for blood cells and blood vessel endothelia. Her discovery faced a great deal ...

GenomeSpace 'recipes' help biologists interpret genomic data

January 20, 2016

Many biomedical researchers are striving to make sense of the flood of data that has followed recent advances in genomic sequencing technologies. In particular, researchers are often limited by the challenge of getting multiple ...

Recommended for you

Online shopping might not be as green as we thought

February 5, 2016

Logic suggests that online shopping is "greener" than traditional shopping. After all, when people shop from home, they are not jumping into their cars, one by one, to travel to the mall or the big box store.

Bright sparks shed new light on the dark matter riddle

February 1, 2016

The origin of matter in the universe has puzzled physicists for generations. Today, we know that matter only accounts for 5% of our universe; another 25% is constituted of dark matter. And the remaining 70% is made up of ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.