The study addresses the complex regulation of HSCs, highlighting p21's multifunctional nature beyond cell cycle control. Through the use of p21-tdTomato mice, researchers differentiate between p21-tdT + and p21-tdT − HSCs. Results show that p21-tdT + HSCs display increased self-renewal and reconstitution abilities.
Zbtb18, upregulated in p21-tdT + HSCs, is crucial for their repopulation capability. p21 interacts with ZBTB18 to suppress cKit, influencing HSC self-renewal. Key findings from the study include: Increased Self-Renewal Capacity in p21-tdT + HSCs: p21-tdT + HSCs exhibit enhanced long-term reconstitution and self-renewal capabilities compared to p21-tdT − HSCs, as evidenced by a higher proportion of resting HSCs (rHSCs) post-myeloablation.
Transcriptional Regulation by p21 and Zbtb18: RNA-seq analysis reveals differential gene expression in p21-tdT + HSCs, with Zbtb18 identified as highly expressed. Zbtb18 knockdown impairs HSC reconstitution, indicating its importance in the self-renewal process. Role of p21 in Transcriptional Repression: p21 interacts with ZBTB18 to co-repress cKit expression, contributing to the regulation of HSC self-renewal independently of its conventional cell cycle inhibitory function.
Cell Division Kinetics of p21-tdT + HSCs: p21-tdT+ HSCs undergo fewer cell divisions than p21-tdT − HSCs, suggesting they are in a relatively inactive state of the cell cycle, which correlates with their enhanced self-renewal capacity. ATAC-seq Analysis R.