Nav: Home

Removing cellular bookmarks smooths the path to stem cells

October 03, 2016

BIRMINGHAM, Ala. - In reading, a bookmark tells where you stopped. Cells use bookmarks too, specific proteins that help the cell remember what collection of genes needs to be turned on again after the brief halt of gene expression during cell division. University of Alabama at Birmingham researchers are exploring the implications removing those bookmarks has on the promise of stem cells.

While the more than 200 different types of human cells all have the same genome, each cell type expresses a different ensemble of genes. These expressions of specific sets of genes make a neuron distinct from a muscle cell, a fibroblast cell -- a cell in connective tissue that produces collagen and other fibers -- or any other type of cell.

Now UAB researchers have found that removing these transcriptional bookmarks may be a key to better reprogramming of human fibroblasts to create induced pluripotent stem cells, or iPS cells. An iPS cell is generated by epigenetic modulation from any somatic cell -- usually skin or blood cells from a child or adult -- to have it behave like an embryonic stem cell. As the name implies, these cells are pluripotent, which means they have the ability to form all adult cell types.

Kejin Hu, Ph.D., an assistant professor in the UAB Department of Biochemistry and Molecular Genetics, calls this de-bookmarking or de-reading. He is able to de-bookmark using small-molecule chemicals that mildly target the binding pockets of the bookmarking proteins, known as bromodomains extra terminal, or BET. The result, Hu says in a paper published in Cell Reports on Sept. 20, is a proof-of-principle strategy to facilitate reprogramming to pluripotency.

Improved reprogramming offers two benefits. First, it may increase the yield of iPS cells created from human fibroblasts, a yield that currently is much lower than reprogramming of mouse cells. Second, it may improve the quality of the iPS cells by ensuring that more of the somatic genes -- those expressed in a differentiated cell, such as a fibroblast -- are efficiently turned down or turned off during reprogramming to the iPS cells.

Quality reprogramming is a vital step in efforts to use iPS cells in medical research and disease treatments. Human iPS cells -- which have the ability to differentiate into any type of specialized cell -- may be able to transform transplantation medicine by creating patient-specific cell-replacement therapies to treat neurological diseases, heart ailments, blood diseases and diabetes.

"Human cells have more than 40,000 genes, but only a portion of the genome is expressed in a specific cell type," Hu said. "This expression of a specific set of genes defines the cell identity. To establish a new cell type -- in my case, a pluripotent stem cell -- we have to erase the old program of gene expression, in addition to establishing the new transcriptional program specific for iPS cells. It's like construction: If you are going to build a new building on the same site, you have to remove the old one first."

The reprogramming factors that are commonly used to create iPS cells from fibroblasts -- based on the breakthrough work of Nobel laureate Shinya Yamanaka in 2006 -- face a reprogramming barrier, Hu says.

"If we can lower the barrier, we can enhance the reprogramming efficiency," Hu said. "My strategy is to use chemicals to erase the transcriptional program specific to the starting cells."

Hu found that a very low concentration of JQ1, an inhibitor of the BET family of proteins:
  • Down-regulated 390 fibroblast-specific genes when applied to naïve human fibroblasts

  • Down-regulated 651 fibroblast-specific genes when applied to human fibroblasts during reprogramming

  • Increased the efficiency of successful reprogramming of human fibroblasts to iPS cells by 20-fold

In support of this gene expression and reprogramming data, fibroblasts change shape when they are treated with JQ1, from a long spindle shape to polygonal or rounded cell, which shows loss of fibroblast identity and transition to pluripotent stem cells. Presumably, genes that are needed to maintain the spindle shape are down regulated by JQ1.

Hu proposes the following model to explain his results. During normal cell division, the active fibroblast genes are bookmarked by attachment of BET proteins to acetylated chromatin during the mitotic phases, while RNA Polymerase II drops off of the chromatin. At the start of interphase, these bookmarks guide the polymerase back to the genes, and they again are transcribed by RNA Polymerase II. In contrast, when JQ1 is added at low concentration, the active fibroblast genes are de-bookmarked by the interaction of JQ1 with the BET proteins during the mitotic phases of cell division. This 'erases' epigenetic memory of the fibroblast gene expression, which in turn results in loss of fibroblast gene transcription when interphase returns. This also increases the success of reprogramming into pluripotent stem cells.

Besides Hu, co-authors of the paper, "Reprogramming by de-bookmarking the somatic transcriptional program through targeting of BET bromodomains," are three co-first authors, Zhicheng Shao, Chunping Yao and Alireza Khodadadi-Jamayran, and Weihua Xu and Tim M. Townes, all of the UAB Stem Cell Institute and Department of Biochemistry and Molecular Genetics; and Michael R Crowley, UAB Department of Genetics, Howell and Elizabeth Heflin Center for Genomic Science.
-end-


University of Alabama at Birmingham

Related Stem Cells Articles:

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.
First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.
Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.
The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.
Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.
New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.
NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.
Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.
In mice, stem cells seem to work in fighting obesity! What about stem cells in humans?
This release aims to summarize the available literature in regard to the effect of Mesenchymal Stem Cells transplantation on obesity and related comorbidities from the animal model.
TSRI researchers identify gene responsible for mesenchymal stem cells' stem-ness'
Researchers at The Scripps Research Institute recently published a study in the journal Cell Death and Differentiation identifying factors crucial to mesenchymal stem cell differentiation, providing insight into how these cells should be studied for clinical purposes.
More Stem Cells News and Stem Cells Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.