A human fetal test is showing progenitor germline cells in green with supporting cells shown in red.
A new study furthers the understanding of the human germline — the cells that create eggs or sperm in humans during prenatal development. The highly specialized germ cells are the only cell type in the body capable of passing parents’ genes on to their biological children. Abnormalities in the germ cells can cause infertility as well as diseases such as germ-cell tumors in young boys and primary ovarian insufficiency in young girls. The study looks closely at how the genetic information of prenatal germ cells is shielded from harm during development, showing that these important cells lack protection that leaves them vulnerable to damage.
“We know very little about how prenatal germline cells are made in the body,” says Amander Clark, PhD, vice chair of molecular, cell and developmental biology and a member of the UCLA Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research. “I am working to understand what they are sensitive to during development and what is protecting them from external environmental factors that could cause them to not work properly.”
A biochemical process that is crucial for protecting human genetic information is called methylation. All healthy human cells are methylated, which acts as a protective coat that safeguards cells from mutations. If cells don’t have methylation, they are vulnerable to damage. Methylation removal, called demethylation, happens infrequently in the human body. One such time is during a short period in prenatal life. This period of germ-cell demethylation was the focus of Dr. Clark’s study, which mapped the amount, duration and location of demethylation in prenatal germ cells from 53 to 137 days of development. The study found that the human germline erases almost all evidence of genome methylation by 113 days of prenatal development. While a large amount of demethylation did occur, some areas of the germ cells retained a small amount of methylation.
“The quality of a person’s germline cells is going to have a huge effect on that person’s ability to have children as an adult,” Dr. Clark says. “Removal of methylation from the germline during prenatal life leaves the germline cells vulnerable to damage. This leads to a critical question: What protects prenatal germline cells from damage or environmental insult during pregnancy?”
Dr. Clark’s model requires her to make human prenatal germline cells from pluripotent stem cells in the lab. In this way, she can study how the germline cells are affected by various factors such as external chemicals or toxins. In the study, Dr. Clark and her team present a detailed ‘reference map’ that contains hundreds of millions of data points. The reference map can be used to ensure that prenatal germ cells created in the lab have the same methylation characteristics as the prenatal germ cells found in a normal human during prenatal life.
“This reference map takes the guess work out of making prenatal germline cells from stem cells,” Dr. Clark says. “Now that we have a high-resolution quantitative analysis of real human germline cells during prenatal life, we can use this information as we make human prenatal germline cells from stem cells for disease-in-a-dish modeling.”
“DNA Demethylation Dynamics in the Human Prenatal Germline,” Cell, June 4, 2015