Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment

Abstract

How hematopoietic stem cells coordinate the regulation of opposing cellular mechanisms like self-renewal and differentiation commitment remains unclear. Here, we identified the transcription factor and chromatin remodeler Satb1 as a critical regulator of the hematopoietic stem cell (HSC) fate. HSCs lacking Satb1 displayed defective self-renewal, less quiescence and accelerated lineage commitment, resulting in progressive depletion of functional HSCs. Increased commitment was caused by reduced symmetric self-renewal and increased symmetric differentiation divisions of Satb1-deficient HSCs. Satb1 simultaneously repressed gene sets involved in HSC activation and cellular polarity, including Numb and Myc, two key factors for stem cell fate specification. Thus, Satb1 is a regulator that promotes HSC quiescence and represses lineage commitment.

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

“…1A). These findings are consistent with our previous report that SATB1 deficiency might affect specification and/or commitment of the lymphoid lineage (32). Indeed, no significant difference was observed in the number of ETPs between WT mice and SATB1 floxed mice with Cre transgenes under the control of the Lck proximal promoter (Lck-Cre), which are active in thymocytes after the DN2 stage (41), although the number of ETPs in Lck-Cre-SATB1 fl/fl mice was lower than that in WT mice (Supplemental Fig.…”

“…The effects of SATB1 deficiency on thymocyte development SATB1 expression is observed in hematopoietic cells as early as the HSC stage (32). In this study, real-time quantitative RT-PCR analysis of thymus tissue indicated that, although all thymocytes of WT mice expressed SATB1 mRNA, the expression level was the highest at the DP stage and decreased thereafter along with maturation ( Fig.…”

“…SATB1 plays a role in the maintenance of self-renewal potential in HSC (32) and in specification/ commitment of HSC/multipotent progenitors to the lymphoid lineage as we previously reported (31), T cell development might be affected at a time point as early as the HSC stage in SATB1cKO mice. However, we did not observe a significant difference in the number of HSCs in the BM between SATB1cKO mice and their WT littermates, which may not be consistent with a previous report by Will et al (32). Because SATB1 null mice die by 3 wk after birth, HPCs from fetal liver or BM in infants were used in the experiments in the previous report, whereas we analyzed adult mice in this study.…”

“…SATB1 forms complexes with SWI/SNF factors and positively and negatively regulates the expression of a vast number of genes (28)(29)(30). SATB1 expression is observed in hematopoietic stem cells (HSCs), and its expression is abundant in thymocytes (31,32). Accordingly, SATB1 and its target genes are involved in various cellular functions in different types of blood cells.…”

“…Accordingly, SATB1 and its target genes are involved in various cellular functions in different types of blood cells. For example, it has been demonstrated that SATB1 is necessary for the self-renewal of HSC (32). SATB1 also plays a role in lymphoid lineage specification and/or commitment (31).…”