Mammary Gland May Have Epigenetic Memory

Epigenomic changes may help explain why mothers produce more milk during second pregnancies than first pregnancies.Rayna Canedy/iStock/Thinkstock.

When a woman becomes pregnant, her body undergoes many changes. Some are caused by increased levels of the hormones prolactin, estrogen, and progesterone. Among the most significant changes are those in the mammary gland, the organ that produces milk.

Several studies have shown that humans and other mammals produce more milk during second pregnancies than first pregnancies. This suggests that the first pregnancy causes a long-lasting change in the mammary gland. However, the structure of the mammary gland is virtually identical in previously pregnant (or “parous”) and never-pregnant (non-parous) animals. One possibility for how this change might occur is that pregnancy alters the organ’s epigenome, the collection of chemical markers that affect how genes are turned on and off, or expressed.

Researchers led by Dr. Gregory J. Hannon at Cold Spring Harbor Laboratory explored this idea. Their work was funded by in part by NIH’s National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI). The study was published in Cell Reports on May 19, 2015.

The researchers first examined the effects of pregnancy hormones on parous and non-parous mice. They exposed mice to estrogen and progesterone at levels similar to those found during pregnancy. They found that the mammary glands of parous mice developed more quickly and showed signs of milk production earlier than those of non-parous mice.

Next, the team looked at how pregnancy affects a type of epigenetic mark called DNA methylation. In mice that had been pregnant or received pregnancy-related hormones, many genes in mammary gland cells had reduced DNA methylation. The changes in DNA methylation in cells involved in milk production were different from those in cells that don’t produce milk. These changes were still present several months later.

The researchers found that the decreased methylation increased the expression of many genes, but only when the mice were exposed to pregnancy-related hormones. This suggests that these changes in DNA methylation only affect gene expression when an animal is pregnant.

Most of the decreased methylation occurred in areas of the genome bound by a transcription factor protein called Stat5a. Transcription factors bind to specific DNA sequences and influence the expression of genes. These findings imply that pregnancy-related changes in DNA methylation alter gene expression by influencing the action of Stat5a.

“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,” says study coauthor Dr. Camila dos Santos.

The researchers are now examining whether similar epigenetic changes might also help explain why pregnancy reduces women’s risk of breast cancer later in life.

—by Brandon Levy