Scientists identify a molecular key that helps cells maintain identity and prevents the conversion of adult cells into induced pluripotent stem cells
They say we can't escape our past--no matter how much we change, we still have the memory of what came before; the same can be said of our cells.
Adult cells, such as skin or blood cells, have a cellular "memory," or record of how the cell changes as it develops from an uncommitted embryonic cell into a specialized adult cell. Now, Harvard Stem Cell Institute researchers at Massachusetts General Hospital (MGH) in collaboration with scientists from the Research Institutes of Molecular Biotechnology (IMBA) and Molecular Pathology (IMP) in Vienna have identified genes that when suppressed effectively erase a cell's memory, making the cell more susceptible to reprogramming and, consequently, making the process of reprogramming quicker and more efficient.
The study was recently published in Nature.
"We began this work because we wanted to know why a skin cell is a skin cell, and why does it not change its identity the next day, or the next month, or a year later?" said co-senior author Konrad Hochedlinger, PhD, an HSCI Principal Faculty member at MGH and Harvard's Department of Stem Cell and Regenerative Biology, and a world expert in cellular reprogramming.
Every cell in the human body has the same genome, or DNA blueprint, explained Hochedlinger, and it is how those genes are turned on and off during development that determines what kind of adult cell each will become. By manipulating those genes and introducing new factors, scientists can unlock dormant parts of an adult cell's genome and reprogram it into another cell type.
However, "a skin cell knows it is a skin cell," said IMBA's Josef Penninger, even after scientists reprogram those skin cells into induced pluripotent stem cells (iPS cells) - a process that would ideally require a cell to "forget" its identity before assuming a new one. Cellular memory is often conserved, acting as a roadblock to reprogramming. "We wanted to find out which factors stabilize this memory and what mechanism prevents iPS cells from forming," Penninger said.
To identify potential factors, the team established a genetic library targeting known chromatin regulators -- genes that control the packaging and bookmarking of DNA, and are involved in creating cellular memory.
Hochedlinger and Sihem Cheloufi, co-first author and a postdoc in Hochedlinger's lab, designed a screening approach that tested each of these factors.
Of the 615 factors screened, the researchers identified four chromatin regulators, three of which had not yet been described, as potential roadblocks to reprogramming. In comparison to the three to four fold increase seen by suppressing previously known roadblock factors, inhibiting the newly described CAF1 (chromatin assembly factor 1) made the process 50 to 200 fold more efficient. Moreover, in the absence of CAF1 reprogramming turned out to be much faster: While the process normally takes nine days, the researchers could detect the first iPS cell after four days.
"The CAF1 complex ensures that during DNA replication and cell division daughter cells keep their memory, which is encoded on the histones that the DNA is wrapped around," said Ulrich Elling, a co-first author from IMBA. "When we block CAF-1, daughter cells fail to wrap their DNA the same way, lose this information and covert into blank sheets of paper. In this state, they respond more sensitively to signals from the outside, meaning we can manipulate them much more easily."
By suppressing CAF-1 the researchers were also able to facilitate the conversion of one type of adult cell directly into another, skipping the intermediary step of forming iPS cells, via a process called direct reprogramming, or transdifferentiation. Thus, CAF-1 appears to act as a general guardian of cell identity whose depletion facilitates both the interconversion of one adult cell type to another as well as the conversion of specialized cells into iPS cells.
In finding CAF-1, the researchers identified a complex that allows cell memory to be erased and rewritten. "The cells forget who they are, making it easier to trick them into becoming another type of cell," said Sihem Cheloufi.
CAF-1 may provide a general key to facilitate the "reprogramming" of cells to model disease and test therapeutic agents, IMP's Johannes Zuber explained. "The best-case scenario," Zuber said, "is that with this insight, we hold a universal key in our hands that will allow us to model cells at will."
BD Colen | EurekAlert!
Barium ruthenate: A high-yield, easy-to-handle perovskite catalyst for the oxidation of sulfides
16.07.2018 | Tokyo Institute of Technology
The secret sulfate code that lets the bad Tau in
16.07.2018 | American Society for Biochemistry and Molecular Biology
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
16.07.2018 | Physics and Astronomy
16.07.2018 | Life Sciences
16.07.2018 | Earth Sciences