SEP 24, 2016 9:27 AM PDT

Removal of 'Bookmarks' Eases Reprogramming of Stem Cells

WRITTEN BY: Carmen Leitch
Cells use proteins as placeholders or bookmarks that help the cells to pick up where they left off when gene expression is halted for a time, something that normally occurs while the cell undergoes division. There are thousands of genes in every cell in the body, but only a small portion of those get expressed at any one time, and whatever set of genes might be on at any time is what can make cells vastly different from one another. Researchers at the University of Alabama Birmingham (UAB) have been studying how those cellular bookmarks that put a cell back in the gene expression place it was impact stem cells, and what removing them can do. 
 


Stem cells hold so much promise because they have the special ability to turn into any type of cell in the body, that specification process is called differentiation. However, the manipulation of those embryonic stem cells has serious ethical implications. As such, researchers have attempted to alter or reprogram differentiated cells in ways that cause them to behave as stem cells, creating induced pluripotent stem cells (iPS cells). It is a process that has not yet been perfected, however. If you would like to know more about the technology, watch the video above in which Nature video presents the technology as its Method of the Year 2009.

Scientists have continued work on the reprogramming technology. Kejin Hu, Ph.D., an Assistant Professor in the Department of Biochemistry and Molecular Genetics at UAB has published proof-of-principle work in Cell Reports demonstrating how small molecules can improve the reprogramming of cells to create iPS cells. The graphical abstract is seen below. The small molecules target binding regions of the bookmarking proteins that put a cell back on the path of gene expression that turns it into a specific tissue type. 
 

"Human cells have more than 40,000 genes, but only a portion of the genome is expressed in a specific cell type," said Hu. "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."

Current technology utilizes reprogramming factors to create iPS cells from fibroblasts, a technique based on the groundbreaking achievements of Nobel laureate Shinya Yamanaka. But there is a barrier to reprogramming barrier, Hu said.

"If we can lower the barrier, we can enhance the reprogramming efficiency," Hu explained. "My strategy is to use chemicals to erase the transcriptional program specific to the starting cells."
Using a low concentration of an inhibitor, JQ1, that affects of a family of proteins called BET, it was observed that 390 genes specific to fibroblasts were down-regulated when JQ1 was applied to naive human fibroblasts. When applied to human fibroblasts undergoing reprogramming, 651 genes specific to fibroblasts were down-regulated, and success of reprogramming was improved 20-fold. The fibroblasts also exhibited changes in physical characteristics, from a spindle to a round or polygonal cells, indicating the loss of identity as a fibroblast.

Hu has proposed a mechanism in which fibroblast proteins are bookmarked by BET proteins, and the application of JQ1 removes those bookmarks during cell division. That in effect removes the epigenetic memory of the cell as fibroblast, such that fibroblastic gene expression does not resume once cell division ends. 

This work could have positive implications for disease treatments and medical research that rely on iPS cells. Ideally, this work would revolutionize transplantation medicine so cell replacement therapies could be tailored to individuals.

Sources: Phys.org via UAB, Nature Biotechnology, Cell Reports
About the Author
  • Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
APR 27, 2021
Neuroscience
Leaky Blood-Brain Barrier Linked to Schizophrenia
APR 27, 2021
Leaky Blood-Brain Barrier Linked to Schizophrenia
Researchers from the University of Pennsylvania have found that people with schizophrenia may have a more permeable bloo ...
MAY 17, 2021
Genetics & Genomics
Diagramming Connections in the Brain with Barcodes
MAY 17, 2021
Diagramming Connections in the Brain with Barcodes
The billions of neurons in the brain form a complex network, as shown in this image from CSHL scientists Xiaoyin Chen an ...
MAY 19, 2021
Cell & Molecular Biology
How Plant Cell Walls Stay Strong but Flexible
MAY 19, 2021
How Plant Cell Walls Stay Strong but Flexible
Plant cell walls have a special ability to expand without breaking or weakening, which is crucial for plant growth. New ...
MAY 19, 2021
Drug Discovery & Development
Combination Immunotherapy Shows Promise in Treating HIV
MAY 19, 2021
Combination Immunotherapy Shows Promise in Treating HIV
  Researchers have found that a new combination immunotherapy, alongside antiretroviral therapy (ART), is effective ...
MAY 23, 2021
Microbiology
Move Over Bacteria, Make Way for Protists
MAY 23, 2021
Move Over Bacteria, Make Way for Protists
In the world of microbes, organisms like viruses and bacteria get a lot of attention. But researchers are beginning to s ...
JUN 16, 2021
Microbiology
DNA - It's What's for Dinner (For Some Bacteria)
JUN 16, 2021
DNA - It's What's for Dinner (For Some Bacteria)
There may be a trillion species of microbes on the planet, so clearly there's still a lot we don't know about these micr ...
Loading Comments...