Ancient viral DNA activates blood cell production during pregnancy and after significant bleeding, researchers discover microbiologystudy

Ancient viral remnants in the human genome are activated during pregnancy and after significant bleeding in order to increase blood cell production, an important step toward defining the purpose of “junk DNA” in humans, according to research from Children’s Medical Center Research Institute at UT Southwestern (CRI) published in Science.

Sean J. Morrison, Ph.D., director of CRI and a Howard Hughes Medical Institute Investigator, and first author Julia Phan, Ph.D., set out to discover how hematopoietic, or blood-forming, stem cells—which typically divide infrequently—are activated during pregnancy and after blood loss.

When they compared activated genes in stem cells from pregnant versus nonpregnant mice, they found retrotransposons had switched on in stem cells from pregnant mice.

Retrotransposons are ancient viral gene sequences now permanently part of our genome and sometimes called “junk DNA” because they don’t encode proteins that contribute to cellular function. They use an enzyme called reverse transcriptase, just like the human immunodeficiency virus (HIV), to replicate themselves.

Humans have evolved mechanisms to keep retrotransposons turned off most of the time, because retrotransposons have the ability to damage DNA when they replicate and reinsert into other parts of the genome.

“It’s the opposite of what we expected. If there’s ever a time to protect the integrity of the genome and avoid mutations, it would be during pregnancy,” Dr. Morrison said.

“There are hundreds of these retrotransposon sequences in our genome. Why not permanently inactivate them, like some species have done? They must have some adaptive value for us.”

Drs. Morrison and Phan used reverse transcriptase inhibiting drugs, commonly used to suppress HIV replication in patients, to inhibit the replication of retrotransposons in mice. These drugs did not alter blood cell production in normal mice but blocked the increase in blood-forming stem cells and red blood cell production during pregnancy, leading to anemia.

As researchers further explored mechanisms activating blood cell production, they found retrotransposons were being detected by the immune sensors, cGAS and STING. These sensors induce interferon production after viral infection or replication of retrotransposons.

“We thought interferon might cause the stem cells to be killed by the immune system. But we found the retrotransposons turned on just enough interferon to activate blood cell production,” said Dr. Phan, a former graduate student in CRI’s Morrison Lab.

When Drs. Phan and Morrison inhibited cGAS, STING, or interferon, there was little or no effect on stem cells or blood cell production in normal mice. But in pregnant mice, this blocked the increase in stem cell numbers and blood cell production, leading to anemia.

Dr. Phan performed similar analyses on blood samples from pregnant women, including three people being treated with reverse transcriptase inhibitors, by collaborating with former Morrison Lab postdoctoral fellow Alpaslan Tasdogan, M.D., Ph.D., now a Professor of Dermatology at University Hospital Essen in Germany. Together, they found retrotransposons and interferon are also activated in human blood-forming stem cells during pregnancy, in addition to being necessary to avoid anemia.

“We are extremely excited that what Dr. Morrison and Dr. Phan discovered in mice is also true in humans. These insights help us understand some of the underlying mechanisms that contribute to anemia during pregnancy,” Dr. Tasdogan said. “Our next step is to initiate a clinical trial to deepen our understanding of how retrotransposons function in patients.”

This research builds on the Morrison Lab’s previous discovery that estrogen contributes to blood-forming stem cell activation during pregnancy.

“This work changes the way we think about mechanisms that regulate tissue regeneration. We’ve only shown it so far in the blood-forming system, but we speculate other kinds of stem cells also co-opt retrotransposons and immune sensors to activate stem cells during tissue regeneration,” Dr. Morrison said.