Dormancy in hematopoietic stem cells (HSCs) is known to maintain HSC function and long-term integrity. Although it was acknowledged that regulating stress responses brought on by HSC activation is crucial for sustaining stem cell function, little was known about the preventative machinery found in human HSCs that may work to avoid their activation and encourage HSC self-renewal. For a study, researchers sought to show that the transcription factor PLAG1 is crucial for long-term HSC activity and that its overexpression results in a 15.6-fold increase in the proportion of functional HSCs under stimulatory circumstances.
PLAG1 inhibits protein synthesis, limits cell growth, and division, and improves survival, according to genome-wide measurements of chromatin occupancy and PLAG1-directed gene expression changes and functional measurements. However, the benefits PLAG1 confer to primitive cells are lessened by the addition of the strong translation activator c-MYC.
They discovered that PLAG1 uses many regulatory mechanisms, including 4EBP1 and translation-targeting miR-127, to guarantee protective decreased protein synthesis and does so independently of stress response signaling. Overall, the research showed that PLAG1 is a key player in the regulation of human HSC dormancy and self-renewal through the extremely context-specific regulation of protein synthesis, and it places PLAG1 within a select group of genuine messenger RNA translation regulators in these cells.
The findings highlighted the significance of the controlled translation control that underlies the physiology of human HSCs, its dysregulation in response to activating demands, and the potential therapeutic value of targeting it.