How epigenetics
affects twins
In genetically identical siblings, DNA methylation and histone acetylation correlate with age and lifestyle
By Charles Q. Choi
The Scientist 7 07 05
The
largest twin study on epigenetic profiles yet reveals the extent to which
lifestyle and age can impact gene _expression_, an international research team reports
in this week's PNAS. Senior
author Manel Esteller
of the Spanish
National Cancer Center in Madrid and colleagues found that 35% of
twin pairs had significant differences in DNA methylation
and histone modification profiles.
"These
findings help show how environmental factors can change one's gene _expression_
and susceptibility to disease, by affecting epigenetics,"
Esteller told The
Scientist.
Esteller and colleagues in Sweden, Denmark, Spain, England, and the United States studied 80 sets of identical twins, ranging in age
from 3 to 74 years. Their aim was to explore what role epigenetics plays in generating phenotypic differences
between genetically identical twins.
The
researchers analyzed the twins' global DNA methylation
and histone H3 and H4 acetylation
in samples from lymphocytes, buccal mucosal
epithelial cells, skeletal muscle biopsies, and subcutaneous fat. They quizzed participants on their health,
nutritional habits, physical activities, drug treatments, and consumption of
tobacco, alcohol, and drugs. They also checked their height and weight.
Statistical
analysis suggested that older twin pairs were more epigenetically different than younger twins. It also
revealed that twins who reported having spent less time together during their
lives, or who had different medical histories, had the greatest epigenetic
differences. Gene
_expression_ microarray analysis revealed that in the two twin pairs most epigenetically distinct
from each other–the 3- and 50-year-olds–there were four times as
many differentially expressed genes in the older pair than in the younger pair,
confirming that the epigenetic differences the researchers saw in twins could
lead to increased phenotypic differences.
Arturas Petronis
of the University
of Toronto, who did not participate in this study, called the
research "excellent" in "quantifying how
genetically identical individuals could differ in gene _expression_ on a global
level due to epigenetics. It is good to have data
that confirms what we long suspected."
Future twin studies can
focus on disease-specific epigenetic effects, Petronis
said.
"There are thousands of cases when there are no
good explanations for different susceptibilities to complex diseases in
individuals with the same genetic background and, in most cases, similar
environments. If we shift our emphasis to epigenetic factors, we can
now come up with some interesting putative mechanisms that would explain such
phenotypic differences," Petronis told The Scientist.
"Maybe some loci are very dynamic
epigenetically, while others are stable."
Randy Jirtle of Duke University Medical Center, who did not participate in this study, suggested investigating
how aging- or lifestyle-related epigenetic changes affect imprinted genes,
which are normally expressed in a parent-of-origin dependent manner.
"For instance, IGF2 is usually only expressed from the father's copy.
People with biallelic _expression_ of IGF2 are more
susceptible to colon cancer, and likely breast cancer and prostate cancer," he told The
Scientist. "So
epigenetic changes due to old age or other factors could lead to overexpression or underexpression
of imprinted genes."
George Martin of the University of Washington in Seattle, who was not involved in this research, cautioned
that future studies needed to look at purified cell types using techniques such
as flow cytometric separation. "As you grow older, you have
shifts in your proportions of cell types—for instance, more memory T
cells and less naive T cells. And you can expect each type to have different
gene _expression_ profiles. So when you work with a mixed tissue sample, you
can't be sure whether a shift in enzyme activity is due to a shift in gene
_expression_ or simply a shift in the proportions of different cell types in the
sample," he told The
Scientist.
Links for this article
L.A. Pray,
"Epigenetics: genome, meet your
environment," The Scientist,
July 5, 2004. http://www.the-scientist.com/2004/7/5/14/1
M.F. Fraga et al., "Epigenetic differences arise during the
lifetime of monozygotic twins," PNAS,
published online July 4, 2005. http://www.pnas.org
Manel Esteller http://groups.cnio.es/epigenetica/indexeng.htm
Arturas
Petronis http://www.utpsychiatry.ca/dirsearch.asp?id=725
Randy Jirtle http://www.geneimprint.com/lab/
M.
Greener, "Cancer epigenetics enters the mainstream,"
The Scientist, June 20,
2005. http://www.the-scientist.com/2005/6/20/18/1
George
Martin http://depts.washington.edu/adrcweb/martin.html
M.L. Phillips, "Epigenetics lives on in clones," The Scientist, February
2, 2005. http://www.the-scientist.com/news/20050202/01
Genes active at time of Xenopus
nuclei transfer are also overexpressed in cloned
embryos
By Melissa Phillips
A cloned Xenopus
embryo overexpressed genes that were being actively
transcribed in its parent cell at the time the nucleus was transferred, according to a study
published in this week's PNAS. This suggests that the embryo "remembers" what type of cell
its nucleus came from, according to study co-author John Gurdon. He and Ray K. Ng of the University of Cambridge report that genes specific to the cell
type of a transferred nucleus are turned on in the wrong tissues of some cloned
embryos at early stages of development.
"The idea
that active gene transcription can be stable through pretty dramatic cell
changes is not new," Paul Wade of the National
Institute of Environmental Health Sciences told The Scientist. "What's new is that it survives nuclear
transfer."
When a somatic nucleus is transferred to an oocyte,
factors in the cytoplasm induce an erasure of the differentiated cell program
in favor of an embryonic transcriptional program.
But the process is not perfect; previous studies have shown that some genes that are silenced in
differentiated cells fail to turn on during reprogramming. Ng and Gurdon
wanted to see if some genes may likewise fail to turn off.
The authors transplanted
nuclei from the Xenopus
embryo neuroectoderm and endoderm into oocytes that had been enucleated by UV radiation. They
dissected the developing embryos into two sections: the animal region, which
develops into neuroectoderm, and the vegetal region,
which will become endoderm.
In a normally developing
embryo, the pan-neural marker Sox2
is highly expressed in the animal region, but found only at background levels
in the vegetal region. In embryos cloned from neuroectoderm
nuclei, the authors found that 17 of 21 samples overexpressed
Sox2 significantly in the vegetal
region; only four of 18 samples showed abnormally high Sox2 _expression_ in the animal region.
They found the converse
effect in embryos derived from endoderm. Edd, an endoderm marker gene, is
usually expressed highly in vegetal regions but not in animal. In the nuclear
transplants, nine of 20 embryos expressed edd more than twice background
levels in the animal region, while vegetal _expression_ was almost entirely
normal.
"The continued _expression_
of somatic cell genes" is not surprising, according to Keith Latham of Temple University. Nonviable clones presumably fail both to turn off
the adult program completely and to turn on the embryonic program completely,
Latham said.
Ng and Gurdon also found
that edd
transcription begins early in most animal regions (eight of 10) and some
vegetal regions (five of 10) of endoderm-derived embryos. They detected edd transcripts
two cell cycles before transcription normally begins in Xenopus, Gurdon said.
Since transcription
normally begins in Xenopus after 12 mitoses, the overexpression of cell type–specific genes means that
the nucleus is "maintaining an active state at a locus in the face of
inactive transcription for 8 to 10 cell cycles, and that is pretty
remarkable," said Wade, who was not involved in the study.
Although they can't be sure
of the molecular mechanism of their findings, Ng and Gurdon speculate that active transcription information could be
inherited through histone modifications.
"There's no known mechanism for replication of a
modified histone," Gurdon said, "but
it seems to be the only plausible explanation."
One of the most striking
findings in the paper is the variability of reprogramming efficiency, according
to Wade. While many embryos overexpressed genes
specific to the transferred nucleus, some embryos seemed to reprogram perfectly.
"This may be an
important component of the variability that one sees in the outcome of nuclear
transfer experiments themselves," Wade told The Scientist. "I think it's potentially quite important
in the variability of the cloning process."
"The fact that
[reprogramming] is not perfect isn't too surprising," Gurdon said.
"In a way, it's amazing that it works at all."
inks for this article
R. Ng, J.B. Gurdon,
"Epigenetic memory of active gene transcription is inherited through
somatic cell nuclear transfer," PNAS,
January 31, 2005. http://www.pnas.org
The Gurdon Group http://www.gurdon.cam.ac.uk/groups/gurdon.html
A. Bortvin
et al., "Incomplete reactivation of Oct4-related genes in mouse embryos cloned
from somatic nuclei," Development,
130:1673-80, April 2003. [PubMed Abstract]
Keith E. Latham http://www.temple.edu/biochemistry_medical/Dr.KLatham.html
