Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How a genetic locus protects adult blood-forming stem cells

26.11.2015

A particular location in DNA, called the Dlk1-Gtl2 locus, plays a critical role in protecting hematopoietic, or blood-forming, stem cells--a discovery revealing a critical role of metabolic control in adult stem cells, and providing insight for potentially diagnosing and treating cancer, according to researchers from the Stowers Institute for Medical Research.

In their study, published online Nov. 25 in Cell Stem Cell, Stowers Investigator Linheng Li, Ph.D., and first author Pengxu Qian, Ph.D., along with other collaborators, reveal how the mammalian imprinted Gtl2, located on mouse chromosome 12qF1, protects adult hematopoietic stem cells by restricting metabolic activity in the cells' mitochondria.


These are MicroRNA clusters expressed from imprinted Gtl2 locus maintain adult hematopoietic stem cells through suppression of mitochondrial biogenesis and metabolic activity.

Credit: Linheng Li Lab

The research focused on imprinted genes--genes "stamped" according to whether they are inherited from the mother or father. With imprinted genes, one working copy, or allele, is inherited instead of two. Either the copy from the mother or father is inactivated or "silenced." Typically, the paternally inherited allele's expression promotes growth, while the maternally inherited allele's expression suppresses it.

The researchers found that when the Gtl2 locus is expressed from the maternally inherited allele, it produces non-coding RNAs to curb metabolic activity. Mechanistically, Gtl2's "megacluster" of microRNA, the largest cluster of microRNA in the mammalian genome, suppresses the mTOR signaling pathway and downstream mitochondrial biogenesis and metabolism, thus blocking mitochondrial-associated byproducts called reactive oxygen species (ROS) that can damage adult stem cells.

"Reactive oxygen species are like the potentially harmful byproducts that come from industrial manufacturing," says Li. "ROS are unavoidable derivatives of the mitochondrial metabolic process and need to be managed by the cell," he explains.

Hematopoietic stems cells renew themselves and differentiate into other cells, including white blood cells, red blood cells, and platelets, constantly renewing the body's blood supply in a process called hematopoiesis. Because of their extraordinary transformative qualities, the transplantation or transfusion of isolated human hematopoietic stem cells has been used in the treatment of anemia, immune deficiencies, and other diseases, including cancer.

While hematopoietic stem cells have gained attention in research, it remains largely unknown how cell metabolic states are controlled. The new findings shed light on the delicate metabolic control required to balance hematopoietic stem cell maintenance and action and the associated healthy hematopoiesis.

An upset in that balance can cause cells to grow abnormally and lead to disease. Abnormalities in the Gtl2 locus on human chromosome 14q32.2 are associated with uniparental disomy in which an individual receives two copies of a chromosome from one parent and no copy from the other parent. Uniparental disomy may cause delayed development, mental retardation, or other medical problems. Differences in gene expression at the Gtl2 locus have also been linked to fetal alcohol exposure disorder.

But when working properly, the Gtl2 locus acts as a great protector of cells.

"Most of the non-coding RNAs at the Gtl2 locus have been documented to function as tumor suppressors to maintain normal cell function," Qian says.

Li's team zeroed in on Gtl2 by studying hematopoietic stem cells in mice with support from Stowers core centers including cytometry, bioinformatics, histology and electron microscopy, molecular biology, and tissue culture. Other collaborators included researchers from the University of Kansas; the University of Kansas Medical Center; Tianjin Medical University, China; Christian Medical College, Vellore, India; Tokyo University of Agriculture, Japan; and University of Cambridge, United Kingdom.

Over the three-year study, investigators used transcriptome profiling to analyze 17 hematopoietic cell types and found that non-coding RNAs expressed from the Gtl2 locus are predominantly located in a subset of the cell types, including adult "long-term" hematopoietic stem cells which have long-term self-renewal capacity. In subsequent experiments, deleting the locus from the maternally inherited allele in hematopoietic stem cells increased mitochondrial biogenesis and subsequent metabolic activity as well as increased ROS levels, with the latter inducing cell death.

The finding opens the possibility for Gtl2 to be used as a biomarker because it could help label dormant (or reserve) stem cells in normal or potentially cancerous stem cell populations, Li says. The addition of a fluorescent tag to the Gtl2 locus could allow researchers to mark other adult stem cells in the gut, hair follicle, muscle, and neural systems.

Other Stowers authors include Xi C. He, M.D., Ariel Paulson, Zhenrui Li, Fang Tao, John M. Perry, Ph.D., Fengli Guo, Ph.D., Meng Zhao, Ph.D., Jeffrey S. Haug, Tari Parmely, and Hua Li, Ph.D.

The research was funded in part by the Stowers Institute for Medical Research, the American Society of Hematology, the National Natural Science Foundation of China and the Natural Science Foundation of Tianjin.

Lay Summary

Hematopoietic stems cells are essential to the healthy functioning of the human body. These cells renew themselves and differentiate into other cells, including white blood cells, red blood cells, and platelets, and constantly renew the body's blood supply. The creation of new blood cells in the body, a process called hematopoiesis, requires a delicate metabolic balance that is not well understood. Stowers Investigator Linheng Li, Ph.D., and colleagues found that the genetic locus Dlk1-Gtl2 plays a critical role in protecting hematopoietic cells by restricting metabolic activity in the cells' mitochondria. This discovery suggests that Gtl2 may be useful clinically as a biomarker to determine if cells are normal or potentially cancerous. The locus' tumor suppression qualities also may lead to future treatments targeting cancer.

###

About the Stowers Institute for Medical Research

The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to basic research - the critical first step in the quest for new medical diagnostics, therapies and treatments. Jim Stowers, founder of American Century Investments, and his wife, Virginia, opened the Institute in 2000. Since then, the Institute has spent over one billion dollars in pursuit of its mission.

Currently, the Stowers Institute is home to 500 researchers and support personnel, over 20 independent research programs, and more than a dozen technology development and core facilities.

Media Contact

Kim Bland
ksb@stowers.org
816-926-4015

 @ScienceStowers

http://www.stowers.org/ 

Kim Bland | EurekAlert!

More articles from Life Sciences:

nachricht Closing the carbon loop
08.12.2016 | University of Pittsburgh

nachricht Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Closing the carbon loop

08.12.2016 | Life Sciences

Applicability of dynamic facilitation theory to binary hard disk systems

08.12.2016 | Physics and Astronomy

Scientists track chemical and structural evolution of catalytic nanoparticles in 3-D

08.12.2016 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>