Reprogramming Adult Cells to Stem Cells Works Better With One Gene Turned Off

 
Wang and his team are the first to identify Jmjd3's role in inhibiting the reprogramming process. They found knockdown or deletion of Jmjd3 in young mouse fibroblasts was enough to greatly enhance reprogramming efficiency

The removal of a genetic roadblock could improve the efficiency of converting adult cells into stem cells by 10 to 30 times, report scientists from The Methodist Hospital Research Institute and two other institutions in the latest issue of Cell.

"The discovery six years ago that scientists can convert adult cells into inducible pluripotent stem cells, or iPSCs, bolstered the dream that a patient's own cells might be reprogrammed to make patient-specific iPSCs for regenerative medicine, modeling human diseases in petri dishes, and drug screening," said Rongfu Wang, Ph.D., Principal Investigator and Director of the Center for Inflammation and Epigenetics. "But reprogramming efficiency has remained very low, impeding its applications in the clinic."

Wang and his group identified a protein encoded by the gene Jmjd3 (also called KDM6B) as a roadblock in the stem cell conversion process. Jmjd3 is known to be involved in many biological processes, including the maturation of nerve cells and immune cell differentiation.

Wang and his team are the first to identify Jmjd3's role in inhibiting the reprogramming process. They found knockdown or deletion of Jmjd3 in young mouse fibroblasts was enough to greatly enhance reprogramming efficiency.

"Our findings demonstrate a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process," said Helen (Yicheng) Wang, co-principal investigator.

In investigating Jmjd3 and its role in iPSC reprogramming, Wang's team found Jmjd3 has two previously unknown functions -- it helps regulate cell growth and cellular aging and Jmjd3 deactivates another nuclear protein, PHF20. The scientists learned during the study that PHF20 is required for cellular reprogramming, because cells without PHF20 failed to generate iPSCs.

"So when it comes to increasing iPSC yields, knocking down Jmjd3 is like hitting two birds with one stone," Rongfu Wang said. Jmjd3 may not be the only genetic roadblock to stem cell conversion. "Removal of multiple roadblocks could further enhance the reprogramming efficiency with which researchers can efficiently generate patient-specific iPSCs for clinical applications," 

Human Y Chromosome Much Older Than Previously Thought

 

Human sex-determining chromosomes: X chromosome (left) and the much smaller Y chromosome

 Mar. 4, 2013 — The discovery and analysis of an extremely rare African American Y chromosome pushes back the time of the most recent common ancestor for the Y chromosome lineage tree to 338,000 years ago. This time predates the age of the oldest known anatomically modern human fossils

University of Arizona geneticists have discovered the oldest known genetic branch of the human Y chromosome -- the hereditary factor determining male sex.
The new divergent lineage, which was found in an individual who submitted his DNA to Family Tree DNA, a company specializing in DNA analysis to trace family roots, branched from the Y chromosome tree before the first appearance of anatomically modern humans in the fossil record.

The results are published in the American Journal of Human Genetics.
"Our analysis indicates this lineage diverged from previously known Y chromosomes about 338,000 ago, a time when anatomically modern humans had not yet evolved," said Michael Hammer, an associate professor in the University of Arizona's department of ecology and evolutionary biology and a research scientist at the UA's Arizona Research Labs. "This pushes back the time the last common Y chromosome ancestor lived by almost 70 percent."

Unlike the other human chromosomes, the majority of the Y chromosome does not exchange genetic material with other chromosomes, which makes it simpler to trace ancestral relationships among contemporary lineages. If two Y chromosomes carry the same mutation, it is because they share a common paternal ancestor at some point in the past. The more mutations that differ between two Y chromosomes the farther back in time the common ancestor lived.

Originally, a DNA sample obtained from an African American living in South Carolina was submitted to the National Geographic Genographic Project. When none of the genetic markers used to assign lineages to known Y chromosome groupings were found, the DNA sample was sent to Family Tree DNA for sequencing. Fernando Mendez, a postdoctoral researcher in Hammer's lab, led the effort to analyze the DNA sequence, which included more than 240,000 base pairs of the Y chromosome.

Hammer said "the most striking feature of this research is that a consumer genetic testing company identified a lineage that didn't fit anywhere on the existing Y chromosome tree, even though the tree had been constructed based on perhaps a half-million individuals or more. Nobody expected to find anything like this."

About 300,000 years ago, the time the Neanderthals are believed to have split from the ancestral human lineage. It was not until more than 100,000 years later that anatomically modern humans appear in the fossil record. They differ from the more archaic forms by a more lightly built skeleton, a smaller face tucked under a high forehead, the absence of a cranial ridge and smaller chins.

Hammer said the newly discovered Y chromosome variation is extremely rare. Through large database searches, his team eventually was able to find a similar chromosome in the Mbo, a population living in a tiny area of western Cameroon in sub-Saharan Africa.
"This was surprising because previously the most diverged branches of the Y chromosome were found in traditional hunter-gatherer populations such as Pygmies and the click-speaking KhoeSan, who are considered to be the most diverged human populations living today."

"Instead, the sample matched the Y chromosome DNA of 11 men, who all came from a very small region of western Cameroon," Hammer said. "And the sequences of those individuals are variable, so it's not like they all descended from the same grandfather."
Hammer cautions against popular concepts of "mitochondrial Eve" or "Y chromosome Adam" that suggest all of humankind descended from exactly one pair of humans that lived at a certain point in human evolution.

"There has been too much emphasis on this in the past," he said. "It is a misconception that the genealogy of a single genetic region reflects population divergence. Instead, our results suggest that there are pockets of genetically isolated communities that together preserve a great deal of human diversity."

Still, Hammer said, "It is likely that other divergent lineages will be found, whether in Africa or among African-Americans in the U.S. and that some of these may further increase the age of the Y chromosome tree."

He added: "There has been a lot of hype with people trying to trace their Y chromosome to different tribes, but this individual from South Carolina can say he did it."
The study came about by combined efforts of a private business, Family Tree DNA, the efforts of a citizen scientist, Bonnie Schrack, and the research capabilities at the UA.

 

Switch That Accelerates Flowering Time Discovered

Crabapple blossoms. With buds bursting early, only for a mild winter to turn Arctic and wipe them out, we are witnessing how warm weather can trigger flowering, even out of season, and how important it is for plants to blossom at the right time of year.

BBSRC-funded scientists have unpicked why temperature has such a powerful affect on how plants flower. In research published in the journal Nature, scientists from the John Innes Centre on the Norwich Research Park have identified the switch that accelerates flowering time in response to temperature.

With warm air, a control gene, called PIF4, activates the flowering pathway, but at lower temperatures the gene is unable to act.

"What is striking is that temperature alone is able to exert such specific and precise control on the activity of PIF4," said Dr Phil Wigge.

Previously, it has been shown that PIF4 is vital for controlling other aspects of plant responses to warmth, for example growth, but this is the first time that the gene has been shown to be necessary for the activation of flowering by temperature.

Flowering is activated by a special molecule, called Florigen. Florigen is activated by many signals, including the longer days of spring. Some plants rely more on temperature, others more on daylength to control key stages in their life cycle such as leaf emergence and flowering. This is reflected in the old saying "Ash before Oak, you're in for a soak; Oak before Ash, you're in for a splash."

While the pathway that activates florigen in response to daylength has been known for many years, how temperature activates Florigen has been a mystery until now.

At lower temperatures, plants do still flower eventually but via other pathways. Any acceleration triggered by PIF4 is lost as it does not bind to and switch on the Florigen gene. As temperatures increase, PIF4 is able to bind the Florigen gene and trigger flowering.

"Our findings explain at the molecular level what we observe in our gardens as the warmer temperatures of spring arrive," said Wigge. "It also explains why plants are flowering earlier as a result of climate change."

Wigge and colleagues hope their research will eventually allow temperature-resilient crops to be developed. Crops plants often respond very strongly to warmer temperatures, reducing yields. By understanding at the molecular levels how plants sense temperature, the team hopes to breed crops which are more resilient to climate change.

"Knowing the key players in the temperature response pathways will be a valuable tool for safeguarding food security in an era of climate change," said Wigge.

With all seven of the warmest years on record in the UK having occurred in the past decade, the race is on to help crops cope with the effects of higher temperatures caused by climate change.

New Way in Which Plants Control Flower Production

 

Flowers don't just catch our eyes, they catch those of pollinators like bees as well. They have to, in order to reproduce. Because plants need to maximize the opportunity for pollinators to gain access to their seeds, variations in the timing of flowering can have profound effects on flower, fruit, and seed production, and consequently agricultural yields.

The major driving forces of flowering are external factors such as light and temperature. However, new research from CSHL Assistant Professor Zach Lippman, Ph.D. and his collaborators, published online November 11 in Nature Genetics, shows there is a second, previously unknown mechanism controlling flowering.

 

Using the tomato plant as their model, Lippman and CSHL co-authors, Cora MacAlister, Soon Ju Park and Ke Jiang, show that loss of control of the timing of flowering, such that the flowering program turns on too fast, results in production of only a single flower on each branch, rather than the usual 7 to 10. Conversely, slowing down the flowering program enables more flowering branches to grow, which means more fruit.

Such dissection of the timing mechanism of flowering in plants like tomato is leading to new strategies for increasing agricultural yield in important crops.

Timing of flowering is precise

During the flowering process, plants form reproductive shoot structures called inflorescences. These structures derive from small stem cell populations buried inside the tiny growing tips of plants called meristems. As plants sense and respond to signals from light and/or temperature, it is at the meristems where plant organs -- leaves or flowers -- are formed.

Domesticated tomato plants, which we know and love for their shiny, tasty red fruit, typically grow several multi-flowered inflorescences on each shoot. Each inflorescence is arranged in a zigzag pattern of 7 to 10 flowers on a single branch. Curiously, many wild species of tomato produce multiple branches on each inflorescence, with each branch having many flowers, thereby increasing the reproductive potential of the plant. In rare cases, genetic mutants of domesticated tomatoes form broom-like inflorescences with dozens of branches like the wild species. Interestingly, there is another class of mutants that produce just a solitary, sometimes abnormal looking, flower.

In previous research Lippman and others reasoned that the timing of flowering would be important in determining whether an inflorescence was highly branched or not. By characterizing the activity of thousands of genes involved in the flowering process of tomato, Lippman and members of his laboratory revealed a "molecular clock" coordinating whether meristems give rise to branched or unbranched inflorescences.

In their newly published research, they reveal that one of those genes plays a critical role in keeping the clock from ticking too fast.

TMF controls synchronization of the flowering transition

"In order for a plant to determine when and where to switch from making leaves to making flowers everything has to be timed perfectly," says Lippman. "We know that the flowering process is regulated by temperature and day length; these control one aspect of the timing. But now we've found a new timing mechanism."

The moment of insight for Lippman and his team, including colleagues at the Unité de Recherche en Génomique Végétale in Evry, France and the Weizmann Institute of Science in Rehovot, Israel, came when studying mutant tomato plants. "We found a gene that when mutated converts the typical tomato multi-flowered inflorescence into one with a single flower," Lippman says. Interestingly, this caused the tomato plant to mimic other single-flowered plants of the same family, called Solanaceae, which includes the eggplant, tobacco, petunia, and pepper plants.

The gene Lippman's team found, called TERMINATING FLOWER (TMF), had not been previously known to have such a crucial role in plant growth. This was despite the fact the flowering process and the genes that control it have been studied in great depth over decades in many plant systems, including the model plant Arabidopsis as well rice and corn (maize).

"It seems TMF regulates a previously unknown pathway that is involved in the timing of flowering. The reason that mutations in TMF cause single-flower inflorescences is that the plant is tricked into thinking it is time to make a flower when it is still in the vegetative state -- the phase of growth that precedes flowering when leaves are still being made," explains Lippman.

Flowering is a tightly coordinated process, so when TMF function is lost the process becomes de-synchronized and uncoordinated. The external signals from light and temperature have not yet reached the critical threshold to tell the plant it is ready to make flowers, yet the program for making flowers starts anyway. Thus TMF acts as an internal check on the flowering transition. "Its normal function is to delay flowering, to gently slow it down, so that it doesn't happen too precociously," Lippman says.

If plants make flowers too quickly, there may not be enough energy from leaves to support those flowers and fruits. But Lippman suggests that some species of plants have taken advantage of this mechanism and evolved to make more or less flowers per inflorescence. It may be that in nature, some plants are more successful when making fewer flowers over a longer period of time, for example.

The Solanaceae species to which tomato belongs contains examples of all types of inflorescences, which is why Lippman finds the model is so fascinating to study. By learning about the genetic switches controlling flower production, the hope is that they can be manipulated in agricultural crops like tomato to improve yield.

Warmer Future Oceans Could Cause Phytoplankton to Thrive Near Poles, Shrink in Tropics

   Phytoplankton in a dark sea; countless numbers drift through the world's oceans.

 By the end of the 21st century, warmer oceans will cause populations of these marine microorganisms to thrive near the poles and shrink in equatorial waters.

"In the tropical oceans, we are predicting a 40 percent drop in potential diversity, the number of strains of phytoplankton," says Mridul Thomas, a biologist at Michigan State University (MSU) and co-author of the journal paper.

"If the oceans continue to warm as predicted," says Thomas, "there will be a sharp decline in the diversity of phytoplankton in tropical waters and a poleward shift in species' thermal niches--if they don't adapt."

Thomas co-authored the paper with scientists Colin Kremer, Elena Litchman and Christopher Klausmeier, all of MSU.

"The research is an important contribution to predicting plankton productivity and community structure in the oceans of the future," says David Garrison, program director in the National Science Foundation's (NSF) Division of Ocean Sciences, which funded the research along with NSF's Division of Environmental Biology.

"The work addresses how phytoplankton species are affected by a changing environment," says Garrison, "and the really difficult question of whether adaptation to these changes is possible."

The MSU scientists say that since phytoplankton play a key role in regulating atmospheric carbon dioxide levels, and therefore global climate, the shift could in turn cause further climate change.

Phytoplankton and Earth's climate are inextricably intertwined.

"These results will allow scientists to make predictions about how global warming will shift phytoplankton species distribution and diversity in the oceans," says Alan Tessier, program director in NSF's Division of Environmental Biology.

"They illustrate the value of combining ecology and evolution in predicting species' responses."

The microorganisms use light, carbon dioxide and nutrients to grow. Although phytoplankton are small, they flourish in every ocean, consuming about half of the carbon dioxide emitted into the atmosphere.

When they die, some sink to the ocean bottom, depositing their carbon in the sediment, where it can be trapped for long periods of time.

Water temperatures strongly influence their growth rates.

Phytoplankton in warmer equatorial waters grow much faster than their cold-water cousins.

With worldwide temperatures predicted to increase over the next century, it's important to gauge the reactions of phytoplankton species, say the scientists.

They were able to show that phytoplankton have adapted to local temperatures.

Based on projections of ocean temperatures in the future, however, many phytoplankton may not adapt quickly enough.

Since they can't regulate their temperatures or migrate, if they don't adapt, they could be hard hit, Kremer says.

"We've shown that a critical group of the world's organisms has evolved to do well under the temperatures to which they're accustomed," he says.

But warming oceans may significantly limit their growth and diversity, with far-reaching implications for the global carbon cycle.

"Future models that incorporate genetic variability within species will allow us to determine whether particular species can adapt," says Klausmeier, "or whether they will face extinction."

Marine Phytoplankton Declining: Striking Global Changes at the Base of the Marine Food Web Linked to Rising Ocean Temperatures

 

Southern Right whale off the coast of Hermanus; South Africa. Phytoplankton forms the basis of the marine food chain and sustains diverse assemblages of species ranging from tiny zooplankton to large marine mammals, seabirds, fish and certain whales.

  A new article published in the 29 July issue of the journal Nature reveals for the first time that microscopic marine algae known as "phytoplankton" have been declining globally over the 20th century. Phytoplankton forms the basis of the marine food chain and sustains diverse assemblages of species ranging from tiny zooplankton to large marine mammals, seabirds, and fish. Says lead author Daniel Boyce, "Phytoplankton is the fuel on which marine ecosystems run. A decline of phytoplankton affects everything up the food chain, including humans."

Using an unprecedented collection of historical and recent oceanographic data, a team from Canada's Dalhousie University documented phytoplankton declines of about 1% of the global average per year. This trend is particularly well documented in the Northern Hemisphere and after 1950, and would translate into a decline of approximately 40% since 1950. 

The scientists found that long-term phytoplankton declines were negatively correlated with rising sea surface temperatures and changing oceanographic conditions.

The goal of the three-year analysis was to resolve one of the most pressing issues in oceanography, namely to answer the seemingly simple question of whether the ocean is becoming more (or less) „green' with algae. Previous analyses had been limited to more recent satellite data (consistently available since 1997) and have yielded variable results. To extend the record into the past, the authors analysed a unique compilation of historical measurements of ocean transparency going back to the very beginning of quantitative oceanography in the late 1800s, and combined these with additional samples of phytoplankton pigment (chlorophyll) from ocean-going research vessels. The end result was a database of just under half a million observations which enabled the scientists to estimate phytoplankton trends over the entire globe going back to the year 1899.

The scientists report that most phytoplankton declines occurred in polar and tropical regions and in the open oceans where most phytoplankton production occurs. Rising sea surface temperatures were negatively correlated with phytoplankton growth over most of the globe, especially close to the equator. Phytoplankton need both sunlight and nutrients to grow; warm oceans are strongly stratified, which limits the amount of nutrients that are delivered from deeper waters to the surface ocean. Rising temperatures may contribute to making the tropical oceans even more stratified, leading to increasing nutrient limitation and phytoplankton declines.

 The scientists also found that large-scale climate fluctuations, such as the El-Niño Southern Oscillation (ENSO), affect phytoplankton on a year-to-year basis, by changing short-term oceanographic conditions.

The findings contribute to a growing body of scientific evidence indicating that global warming is altering the fundamentals of marine ecosystems. Says co-author Marlon Lewis, "Climate-driven phytoplankton declines are another important dimension of global change in the oceans, which are already stressed by the effects of fishing and pollution. Better observational tools and scientific understanding are needed to enable accurate forecasts of the future health of the ocean." Explains co-author Boris Worm, "Phytoplankton are a critical part of our planetary life support system. They produce half of the oxygen we breathe, draw down surface CO₂, and ultimately support all of our fisheries. An ocean with less phytoplankton will function differently, and this has to be accounted for in our management efforts."

Bio-Crude Turns Cheap Waste Into Valuable Fuel

 

Forest waste can be converted into bio-crude oil. 

CSIRO and Monash University have developed a chemical process that turns green waste into a stable bio-crude oil. The bio-crude oil can be used to produce high value chemicals and biofuels, including both petrol and diesel replacement fuels.

“By making changes to the chemical process, we’ve been able to create a concentrated bio-crude which is much more stable than that achieved elsewhere in the world,” says Dr Steven Loffler of CSIRO Forest Biosciences.

“This makes it practical and economical to produce bio-crude in local areas for transport to a central refinery, overcoming the high costs and greenhouse gas emissions otherwise involved in transporting bulky green wastes over long distances.”

The process uses low value waste such as forest thinnings, crop residues, waste paper and garden waste, significant amounts of which are currently dumped in landfill or burned.

“By using waste, our Furafuel technology overcomes the food versus fuel debate which surrounds biofuels generated from grains, corn and sugar,” says Dr Loffler.

“The project forms part of CSIRO’s commitment to delivering cleaner energy and reducing greenhouse gas emissions by improving technologies for converting waste biomass to transport fuels.”

The plant wastes being targeted for conversion into biofuels contain chemicals known as lignocellulose, which is increasingly favoured around the world as a raw material for the next generation of bio-ethanol.

Lignocellulose is both renewable and potentially greenhouse gas neutral. It is predominantly found in trees and is made up of cellulose; lignin, a natural plastic; and hemicellulose.

CSIRO and Monash University will apply to patent the chemical processes underpinning the conversion of green wastes to bio-crude oil once final laboratory trials are completed.

The research to date is supported by funding from CSIRO’s Energy Transformed Flagship program, Monash University, Circa Group and Forest Wood Products Australia.

National Research Flagships CSIRO initiated the National Research Flagships to provide science-based solutions in response to Australia’s major research challenges and opportunities. The nine Flagships form multidisciplinary teams with industry and the research community to deliver impact and benefits for Australia.