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Keywords:

  • epigenetic repression;
  • hematopoietic stem cell;
  • lineage differentiation;
  • protein inhibitor of activated STAT1;
  • self-renewal

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−/− 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.

Synopsis

Thumbnail image of graphical abstract

Novel genetic results establish the ubiquitin E3-ligase PIAS1 as epigenetic regulator of HSC-dormancy and lineage restriction by direct repression of Gata1.

  • PIAS1 maintains the quiescent state of dormant hematopoietic stem cells (HSCs).
  • PIAS1 protects the self-renewal potential of HSCs.
  • PIAS1 prevents the inappropriate expression of the erythroid transcription factor Gata1 through epigenetic silencing.
  • PIAS1 balances the differentiation programs between myeloid and lymphoid lineages.