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 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.
