One of the four ingredients in the genetic recipe that scientists in Japan and the U.S. followed last year to persuade human skin cells to revert to an embryonic stem cell state, is dispensable in ES cells, thanks to the presence of a molecular alliance between a specific group of key proteins known as transcription factors, a research team led by the Genome Institute of Singapore (GIS) under the Agency for Science, Technology and Research (A*STAR) reports in the current issue of Nature Cell Biology.
The reprogramming factor - Klf4, one of the transcription factors that determine whether a cell's genes are active or silent - has at least two other sibling molecules that will substitute Klf4 to maintain a pluripotent embryonic stem (ES) cell state, the GIS-led team said.
Klf4 (also known as gut-enriched Krüppel-like factor or Gklf) belongs to the Krüppel-like factor (Klf) family of transcription factors that regulate numerous biological processes including proliferation, differentiation, development and apoptosis, or programmed cell death.
Since reprogramming mature cells to the ES state may provide a ready source of tissue for biomedical research and clinical treatment of diseases such as Parkinson's and diabetes, several laboratories, including GIS, are trying to better understand and finely tune the reprogramming process.
The team looks for clues for what these reprogramming ingredients are doing in ES cells.
"Klf4 has been a mysterious player among the four reprogramming factors. As taking out Klf4 in ES cells did not have any apparent effects, it is difficult to reconcile why such a potent reprogramming factor has no role in ES cell biology," said GIS scientist Ng Huck Hui, Ph.D., who headed the research team. Other members of the team include researchers from the National University of Singapore and University of Illinois at Urbana-Champaign.
The GIS research team found that when Klf4 was depleted, Klf2 and Klf5 took over Klf4's role. To understand the molecular basis of the Klf4 redundancy, the scientists studied the DNA binding and transcription activation properties of the three Klfs and found that the profiles of the three Klfs were strikingly similar.
"Most important, the data showed that the other Klfs were bound to the target sites when one of them was depleted." said Dr. Ng. "These Krüppel-like factors form a very powerful alliance that work together on regulating common targets. The impact of losing one of them is masked by the other two sibling molecules."
For example, Klfs were found to regulate the Nanog gene and other key genes that must be active for ES cells to be pluripotent, or capable of differentiating into virtually any type of cells. Nanog gene is one of the key pluripotency genes in ES cells.
"We suggest that Nanog and other genes are key effectors for the biological functions of the Klfs in ES cells," Dr. Ng said.
"Together, our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression unique to ES cells.
The way these factors network with key genes in ES cells suggest a way of how Klf4 (along with the other three reprogramming factors) can jump-start the ES cell gene expression engine in adult cells," he noted.
Although these three Klfs are involved in diverse biological roles, their redundant roles have not been previously appreciated.
"Dr. Ng and his colleagues at the Genome Institute of Singapore again have unraveled another intricacy of what makes a stem cell," said Edison Liu, M.D., Executive Director of GIS. "This work brings us closer to a detailed understanding of the genetic components of stemness."
Alan Colman, Ph.D., internationally recognized leader in stem cell research, said, "Klf4 is a transcription factor that came to prominence recently because it was one of four factors used to reprogram somatic cells back to the pluripotent state seen in embryonic stem cells.
"The mystery of the role of Klf4 has been revealed in studies by Huck Hui and colleagues," added Colman, Executive Director of the Singapore Stem Cell Consortium, which like GIS, is part of Singapore's A*STAR. "They show for the first time that Klf4 itself is not needed for the maintenance of the pluripotent state in ES cells; however, this is because the cells have a number of other Klf-like transcription factors that can substitute for Klf4."
For enquiries, please contact the following:Genome Institute of Singapore
Cathy Yarbrough | EurekAlert!
Exciting Plant Vacuoles
14.06.2019 | Julius-Maximilians-Universität Würzburg
A microscopic topographic map of cellular function
13.06.2019 | University of Missouri-Columbia
Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.
Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...
Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.
The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...
Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.
The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....
Researchers at Chalmers University of Technology, Sweden, have discovered a completely new way of capturing, amplifying and linking light to matter at the nanolevel. Using a tiny box, built from stacked atomically thin material, they have succeeded in creating a type of feedback loop in which light and matter become one. The discovery, which was recently published in Nature Nanotechnology, opens up new possibilities in the world of nanophotonics.
Photonics is concerned with various means of using light. Fibre-optic communication is an example of photonics, as is the technology behind photodetectors and...
Fraunhofer IZM is joining the EUROPRACTICE IC Service platform. Together, the partners are making fan-out wafer level packaging (FOWLP) for electronic devices available and affordable even in small batches – and thus of interest to research institutes, universities, and SMEs. Costs can be significantly reduced by up to ten customers implementing individual fan-out wafer level packaging for their ICs or other components on a multi-project wafer. The target group includes any organization that does not produce in large quantities, but requires prototypes.
Research always means trying things out and daring to do new things. Research institutes, universities, and SMEs do not produce in large batches, but rather...
29.04.2019 | Event News
17.04.2019 | Event News
15.04.2019 | Event News
14.06.2019 | Information Technology
14.06.2019 | Materials Sciences
14.06.2019 | Medical Engineering