Repetitive elements trigger RIG-I-like receptors to enhance hematopoietic stem cell formation
Hematopoietic stem cells can replenish all the different cell types of our blood system. For this reason, hematopoietic stem cells are the cells used in many blood diseases when patients need transplantations. Thus, our ability to generate, amplify and maintain these cells is important for human health. The lab of Eirini Trompouki at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, in collaboration with scientists the Albert Einstein College of Medicine, the University of Trento and the Chinese Academy of Sciences, discovered a novel mechanism that enhances hematopoietic stem cell formation during development. They showed that RNA from repetitive elements, remnants of viruses integrated through evolution into the genome of many animals, is produced during hematopoietic development. Repetitive element RNAs activate innate immune receptors to induce inflammation—the good kind—and increase the formation of embryonic hematopoietic stem cells.
Hematopoietic stem cells are the foundation of the blood system from fish to humans and give rise to leukocytes for fighting off pathogens, erythrocytes for transferring oxygen to tissues, and every other cell type that can be found in our blood. Importantly, hematopoietic stem cells born during development are also the foundation of our blood system when we are adults and their improper function can lead to multiple blood diseases. Therefore, hematopoietic stem cells are precious both in sickness and in health and understanding the mechanisms that govern their formation during development can help simply: “make blood.”
Repetitive element RNA enhances HSC formation
During the process of embryonic hematopoiesis in zebrafish, the lab of Eirini Trompouki found small bits of RNA expressed from a part of the genome considered as ‘junk DNA.’ “Contrary to what many people believe, genes only comprise a very small part of our genome. The largest part of it contains other sequences, among which many are the remnants of viruses accumulated within the vertebrate genome through years of infections and evolution. Such sequences are for example several types of the so-called repetitive elements that usually remain repressed,” explains Eirini Trompouki, Max Planck group leader and member of the Centre for Integrative Biological Signalling Studies, Cluster of Excellence at the University of Freiburg.
To investigate the possible role of these RNA molecules in hematopoietic stem cell formation, the team used chemicals that enhance the expression of repetitive elements or injected a repetitive element copy RNA in zebrafish embryos. These experiments resulted in an increase in hematopoietic stem cell numbers generated within injected embryos. The next question of the team was how do repetitive elements exert their function in hematopoietic development? They hypothesized that, since these RNAs are viral remnants, they might be sensed by cell proteins that are normally used to sense everyday viral infections.
One of the key sensors of viral infection is the RIG-I-like receptor (RLR) family, which establishes a host response once activated by such a pathogen. Eirini and her team thought that in order to prove that repetitive elements are sensed by RLRs they needed to show that the increase in HSC numbers, observed upon chemical induction or overexpression of repetitive elements should not happen if RLRs are missing from the cells. Indeed, the team showed that injection of the same repetitive element RNA copy could not enhance hematopoietic stem cell development in RLR-deficient zebrafish embryos, which proved that the influence of these RNAs on hematopoietic stem cell generation depends on the presence and function of RLRs.
https://medicalxpress.com/news/2020-11-repetitive-elements-trigger-rig-i-like-receptors.html
