Ananya Ghosal, MAKAUT (WB)
Chemotherapy is used to treat cancer patients. During the process of chemotherapy, the effects of the chemotherapeutic agent are to reduce or kill the cancer cells but besides cancer cells, other cell types are also affected which includes cycling blood cells. This process puts the hematopoietic system under pressure and sends hematopoietic stem cells in the bone marrow, producing fresh cells and fill up the stable pool of differentiated blood cells in the body.
To enhance activation after chemotherapy, hematopoietic stem cells use RNA molecules from junk DNA. Despite hematopoietic stem cells being inactive, they have evolved a mechanism to respond to stress. During early recovery, the increase in transcription of transposable elements reorganizes Robust chromatin. The generation of inflammatory response is important for hematopoietic stem cells to get activated by binding transposable transcript to immune receptor MDA5.
Inflammation of hematopoietic stem cell:
In the hematopoietic hierarchy, hematopoietic stem cell lines on the top give rise to most of the blood cells including immune cells. For the prevention of stem cell exhaustion and preserve the long-term self-renewal potential, hematopoietic stem cell is kept dormant in the bone marrow. After chemotherapy, they are “forced” to exit dormant and start cycling. By starting proliferation, hematopoietic stem cells respond to chemotherapy. For the activation of hematopoietic stem cells, inflammatory signal plays an important role.
The Link between junk RNA and chemotherapy-induced inflammation:
In hematopoietic stem cells, the RNAs of classic coding genes besides other RNA molecules are transcribed after chemotherapy. This part of the RNAs stems from inactive or active transposable elements. Through millions of years of evolution, the remaining pathogens like bacteria and viruses that are integrated into the genome are transposable elements. Human and mouse genomes are dominated by the large strands of genetic material by more than 1/3rd although it appears to lack particular functions, that is “junk DNA”.
The transposable elements activate an immune receptor and make RNA after chemotherapy which causes inflammatory signaling by increasing hematopoietic stem cell cycling and results in the regeneration of the hematopoietic system. The Hematopoietic stem cell is primarily related to the immune cells and some receptors induce inflammation and their function is to sense viral RNA. The transposable element RNA can bind to MDA5 (immune receptor) and trigger an inflammatory response, leading to exiting inactivity and begin proliferating. Hematopoietic stem cells become less efficient and slower without this interaction. This specifies RNA sensing helps to increase blood regeneration after chemotherapy but is not important for hematopoietic regeneration.
Mechanism:
The cells during developmental transition use transposable element RNA. The alteration from inactive to active proliferative state means a huge reorganization of the genome like the cell needs to turn on essential for the increase in cell cycling and metabolism and switch of genes which are responsible for energy-saving mode. To adjust or adapt whenever cells need to change their state, they use repetitive RNAs or transposable elements after stress for example chemotherapy or any physiological stress signals like aging or development. The use of RNA is a pathway for the cell to buffer transcription and sense.
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Reference-
- Clapes, T., Polyzou, A., Prater, P., Sagar, Morales-Hernández, A., Ferrarini, M. G., Kehrer, N., Lefkopoulos, S., Bergo, V., Hummel, B., Obier, N., Maticzka, D., Bridgeman, A., Herman, J. S., Ilik, I., Klaeylé, L., Rehwinkel, J., McKinney-Freeman, S., Backofen, R., … Trompouki, E. (2021). Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration. Nature Cell Biology, 23(7), 704–717. https://doi.org/10.1038/s41556-021-00707-9
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