Ezh2 restricts activation of fetal gene signature in adult hematopoietic stem and progenitor cells. Mus musculus

Fetal liver hematopoietic stem cells seed bone marrow (BM) and undergo reprograming into adult type that are largely quiescent and restricted in their self-renewal activity. Here we show that in the absence of the polycomb-group gene Ezh2, a cohort of fetal-specific genes, including let-7 target genes, were activated in BM hematopoietic stem and progenitor cells (HSPCs), leading to acquisition of fetal phenotypes by BM HSPCs, such as enhanced self-renewal activity and production of fetal-type lymphocytes. The Lin28b-let-7 pathway determines developmentally timed changes in HSPC programs. Of note, many of the fetal-specific let-7 target genes, including Lin28, appeared to be transcriptionally repressed by Ezh2-mediated H3K27me3 in BM HSPCs, and Ezh2 loss resulted in their ectopic expression, particularly in hematological malignancies that develop in the absence of Ezh2. These findings suggest that Ezh2 cooperates with let-7 microRNAs in silencing fetal gene signature in BM HSPCs and restricts their transformation.