PIAS1 SUMO ligase regulates the self-renewal and differentiation of hematopoietic stem cells

Abstract

The selective and temporal DNA methylation plays an important role in the self-renewal and differentiation of hematopoietic stem cells (HSCs), but the molecular mechanism that controls the dynamics of DNA methylation is not understood. Here, we report that the PIAS1 epigenetic pathway plays an important role in regulating HSC self-renewal and differentiation. PIAS1 is required for maintaining the quiescence of dormant HSCs and the long-term repopulating capacity of HSC. Pias1 disruption caused the abnormal expression of lineage-associated genes. Bisulfite sequencing analysis revealed the premature promoter demethylation of Gata1, a key myeloerythroid transcription factor and a PIAS1-target gene, in Pias1 À/À HSCs. As a result, Pias1 disruption caused the inappropriate induction of Gata1 in HSCs and common lymphoid progenitors (CLPs). The expression of other myeloerythroid genes was also enhanced in CLPs and lineage-negative progenitors, with a concurrent repression of B cell-specific genes. Consistently, Pias1 disruption caused enhanced myeloerythroid, but reduced B lymphoid lineage differentiation. These results identify a novel role of PIAS1 in maintaining the quiescence of dormant HSCs and in the epigenetic repression of the myeloerythroid program.

B Cell Receptor Activation and Chemical Induction Trigger Caspase-Mediated Cleavage of PIAS1 to Facilitate Epstein-Barr Virus Reactivation

“…PIAS1 was reported to directly associate with cellular promoters (Liu et al, 2010; Liu et al, 2014b; Toropainen et al, 2015). We reasoned that PIAS1 may also interact with viral promoters in EBV-infected cells.…”

“…Subsequent studies indicated that all PIAS proteins have Small Ubiquitin-like MOdifier (SUMO) E3 ligase activity with the ability to SUMOylate both viral and cellular proteins to alter their functions (Chang et al, 2004; Kahyo et al, 2001; Kim et al, 2014; Lee et al, 2003). More recent studies suggest that PIAS1 functions as an epigenetic regulator in the self-renewal and differentiation of hematopoietic stem cells, the differentiation of regulatory T cells, and breast tumorigenesis (Liu et al, 2010; Liu et al, 2014a; Liu et al, 2014b). PIAS1 also functions as a chromatin-bound co-regulator for the androgen receptor (Toropainen et al, 2015).…”

The Role of PIAS SUMO E3-Ligases in Cancer

“…Initially identified as a component of the PML-RARA oncoprotein of t(15;17) of acute promyelocytic leukemia (APL), PML tumor suppressor is frequently lost in human cancer through aberrant ubiquitin-proteasomal degradation triggered by CK2 (37,38). PIAS1 and PIASx-α are PML SUMO E3-ligases (21).…”

Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes

“…To further address whether Uhrf1 plays a role in the establishment of the DNA methylation patterns of erythroid-specific genes, we performed bisulfite sequencing to assess the DNA methylation levels of several up-regulated erythroid-specific genes in Uhrf1-deficient FL-HSPCs. The CpG sites around the transcription start sites of Gata1, Gfi1b, and Car1, which are critical for regulating the expression of these genes (11,31,32), showed decreased DNA methylation levels compared with those in WT controls (Fig. 5 A and B).…”