MAMMARY GLAND REMEMBER'S PRIOR PREGNANCY , SPURRING MILK PRODUCTION
Anecdotal reports of
nursing mothers have long suggested that giving milk is a lot easier in second
and subsequent pregnancies, compared with a first pregnancy. Now, researchers
at Cold Spring Harbor Laboratory (CSHL) are able to explain why
Their work shows the
mammary gland forms a long-term memory of pregnancy that primes it to respond
to the hormonal changes that announce succeeding pregnancies. The memory lasts
throughout an individual's reproductive years. The results appear online in Cell
Reports.
Secretion of the
hormones estrogen and progesterone set the stage for dramatic changes that take
place in the breast during pregnancy: a massive proliferation of mammary
epithelial cells, and the formation of thousands of ductal structures, which
support milk production and transport during lactation.
A team led by HHMI
Investigator Greg Hannon, a CSHL Professor and also a Professor and Senior
Group Leader at the CRUK Cambridge Institute at the University of Cambridge,
hypothesized that pregnancy might alter the gland's receptiveness to
pregnancy-related hormones. Specifically, they sought to determine if this
might occur via changes in a set of chemical marks that attach to DNA, the
genetic material. Such marks -- molecules of methyl (CH3), for instance -- are
called epigenetic marks, and their presence or absence in particular locations
in the genome can either prevent genes from being expressed, or promote their
expression.
Camila dos Santos, now
a CSHL Assistant Professor, developed a technique critical to the newly
reported experiments when she was a postdoctoral investigator in the Hannon
lab. Dos Santos found a marker of mammary stem cells that enabled her to
isolate highly purified stem cells in addition to a number of other cell types
specific to the mouse mammary gland -- six in all. From these, she generated
genome-wide profiles of where methyl groups attach to the DNA. Of all the
epigenetic marks, methyl marks tend to be the longest lasting, and are often
permanent.
Working with Andrew
Smith, a computational biologist from the University of Southern California,
they found that cells sampled from young mice that had been through a single
pregnancy cycle had methylation marks that were "substantially
different" from marks in cells sampled from mice of the same age that had
never been pregnant. "Of those changes," says Hannon, "we were
able to trace a majority to places in the genome where a single transcription
factor, called Stat5a, binds. This is really remarkable -- so many changes in
methylation, and you can track them down to a single factor." Like all
transcription factors, Stat5a binds to DNA and in so doing changes the way a
specific gene or genes are expressed.
The team shows that a
first pregnancy erases many methyl marks that are present throughout life
leading up to pregnancy. During a first pregnancy, the team suggests, Stat5a
binds DNA in certain types of mammary epithelial cells, at places near genes
that need to be activated during pregnancy -- specifically, genes involved in
proliferation and lactation. As the team showed in mice, when a once-pregnant
female receives hormones whose action simulates a real pregnancy, the mice
respond more rapidly than other, never-pregnant mice given the same hormones.
In the previously pregnant mice, "the mammary glands start expanding
faster and also sooner than for those experiencing pregnancy hormones for the
first time," says dos Santos. "It's as if the gland already knows
those hormones."
"This is an
example of epigenetic memory: it is the loss of DNA methylation that is now
marking sites in the genome that were active in a previous pregnancy," dos
Santos says. When the same sites were examined a year after pregnancy (or
exposure to pregnancy hormones), they remained unoccupied by methyl marks. "The
cell is not replenishing DNA methylation at these sites, even after several
cell divisions, which means the memory of previous pregnancy is
long-term."
These findings have
led to another important line of research. It is well known that women who
become pregnant by age 25 have substantially lower rates of breast cancer than
women who bear children later in life or not at all. It is possible that the
implied protective factor is in some way related to the epigenetic memory of
mammary cells just discovered, Hannon says.
Dos Santos says her lab is
now "trying to understand which of the modifications we found in this
study might prevent development of breast cancer in a pregnancy-related
manner."
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