Detection of “junk” RNA after chemotherapy improves blood regeneration


Under homeostatic conditions, HSCs are at rest in the bone marrow. After chemotherapy, the transposable element (TE) increases RNA and activates the innate immune receptor MDA5. This leads to the induction of inflammatory signals that help HSCs to break out and begin to proliferate in order to replenish differentiated blood cells that were removed by chemotherapy. Credit: Max Planck Institute for Immunobiology and Epigenetics

Chemotherapy is widely used to treat cancer patients. During treatment, chemotherapeutic agents affect various biochemical processes to kill or reduce the growth of cancer cells, which divide uncontrollably in patients. However, the detrimental effect of chemotherapy cells affects cancer cells, but also in principle many other cell types, including cycling blood cells. This causes the hematopoietic system to be subjected to strong stress and pushes the hematopoietic stem cells (HSCs) into the bone marrow to produce fresh cells and replenish the stable set of differentiated blood cells in the body.

Researchers at the MPI for Immunobiology and Epigenetics, along with colleagues at the University of Freiburg, Lyon, Oxford and St Jude Children’s Research Hospital in Memphis, have now discovered that make use of RNA molecules from junk DNA sections to enhance their subsequent activation .

Inflammation of awakening by HSC

Hematopoietic stem are at the top of the hematopoietic hierarchy and can give rise to most including immune cells. Under normal conditions, HSCs remained latent in the to preserve its long-term self-renewal potential and prevent stem cell depletion. However, after chemotherapy, they are “forced” to quit quiescence and start cycling. “Hematopoietic stem cells respond to chemotherapy as they begin to proliferate. We know that inflammatory signaling is critical for HSC activation, but we still don’t fully understand how this happens,” says Eirini Trompouki, group leader at MPI of Freiburg Immunobiology and Epigenetics.

A link between chemotherapy-induced inflammation and debris RNA

Interestingly, she and her team observed that other RNA molecules, in addition to the RNAs in the “classic” coding genes, are transcribed into HSC after chemotherapy. Some of this RNA comes from active or inactive transposable elements. Transposable elements are remnants of pathogens such as viruses or bacteria that have been integrated into the genome over millions of years of evolution. Researchers often considered these extensive strands of genetic material to dominate the human and mouse genomes by more than a third, but they do not appear to have specific functions, such as “junk DNA.”

Once the team noticed that the RNA of these elements increases after chemotherapy, the question was asked: “Is there a link between the RNA of the transposable element and the increase in inflammatory signals observed after of chemotherapy? ” explains Thomas Clapes, lead author of the study. In fact, HSCs express some receptors that could induce inflammation, but are primarily associated with and its role is to detect viral RNA. “We hypothesized that these receptors could also bind to the transposable element of RNA,” says Aikaterini Polyzou. The scientists ’data show that the RNA of the transposable element can bind to the MDA5 immune receptor and elicit an inflammatory response that causes HSCs to break out and begin to proliferate. “Without these interactions, HSC activation becomes slower and less efficient. This indicates that RNA detection is probably not necessary for hematopoietic regeneration, but helps to improve blood regeneration after chemotherapy. “, say Clapes, Polyzou and Pia Prater.

Mechanism or adaptation?

These results help to better understand the molecular foundations of hematopoietic regeneration, especially after chemotherapy. However, the results also indicate that the RNA of the transposable element is used by cells during developmental transitions. The transition of a cell from an inactive-rest state to an active proliferative state means a massive reorganization of the genome. For example, the cell must turn off genes responsible for the energy-saving mode and activate genes essential to increase metabolism or the cell cycle. “It’s interesting to think that cells use it or other repetitive RNAs to refine and adapt whenever they need to change their state, for example after stress, such as chemotherapy, or even after signs of physiological stress such as development or aging. “says Trompouki. Scientists assume that the use of RNA is a way of” We have much more to know whether RNA detection is an evolutionary adaptation that is used in cases of high cellular plasticity to fine-tune the decisions of the fate of the cells, ”says Trompouki.

Repetitive elements activate RIG-I-like receptors to enhance hematopoietic stem cell formation

More information:
Thomas Clapes et al, Chemotherapy-induced transposable elements activate MDA5 to enhance hematopoietic regeneration, Nature Cell Biology (2021). DOI: 10.1038 / s41556-021-00707-9

Citation: Detection of “junk” RNA after chemotherapy improves blood regeneration (2021, July 12) recovered on July 12, 2021 at chemotherapy-blood-regeneration.html

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