Polycomb group ring finger 1 cooperates with Runx1 in regulating differentiation and self-renewal of hematopoietic cells

Abstract

<jats:title>Abstract</jats:title><jats:p>The transcription factor runt-related transcription factor 1 (Runx1) is essential for the establishment of definitive hematopoiesis during embryonic development. In adult blood homeostasis, Runx1 plays a pivotal role in the maturation of lymphocytes and megakaryocytes. Furthermore, Runx1 is required for the regulation of hematopoietic stem and progenitor cells. However, how Runx1 orchestrates self-renewal and lineage choices in combination with other factors is not well understood. In the present study, we describe a genome-scale RNA interference screen to detect genes that cooperate with Runx1 in regulating hematopoietic stem and progenitor cells. We identify the polycomb group protein Pcgf1 as an epigenetic regulator involved in hematopoietic cell differentiation and show that simultaneous depletion of Runx1 and Pcgf1 allows sustained self-renewal while blocking differentiation of lineage marker–negative cells in vitro. We found an up-regulation of HoxA cluster genes on Pcgf1 knock-down that possibly accounts for the increase in self-renewal. Moreover, our data suggest that cells lacking both Runx1 and Pcgf1 are blocked at an early progenitor stage, indicating that a concerted action of the transcription factor Runx1, together with the epigenetic repressor Pcgf1, is necessary for terminal differentiation. The results of the present study uncover a link between transcriptional and epigenetic regulation that is required for hematopoietic differentiation.</jats:p>

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

“…In addition, ChIP-seq analysis of embryonic stem (ES) cells revealed that KDM2B was enriched near transcription start sites, including Hox gene loci (7). These data were consistent with the findings that DNA methylation strongly excludes the recruitment of BCOR complex components (9) and that PCGF1 regulates Hox expression (10,11).…”

“…2B); however, the prognostic value of BCORL1 mutations remains unclear. Notably, BCORL1 depletion increased the replating capacity of Runx1-depleted Lin À cells (11). These results suggest that BCORL1 dysregulation may be a cause of myeloid malignancy.…”

“…1). Ross and colleagues observed a strong gain in self-renewal and a block in differentiation in lineagemarker negative (Lin À ) cells that were simultaneously depleted of Pcgf1 and Runx1 (11). These data indicated that Pcgf1 primes hematopoietic progenitors for differentiation through H2AK119 monoubiquitylation on HoxA cluster genes, thus leading to the inhibition of HoxA transcription (11).…”

The Role of Polycomb Group Proteins in Hematopoietic Stem Cell (HSC) Self-Renewal and Leukemogenesis

“…Depletion of KDM2B resulted in derepression, a loss of RING1B binding and decreased H2AK119ub levels at these target genes. In mouse hematopoietic cells, PCGF1 was picked up as a factor negative regulating self-renewal of lineage negative cells in a Runx1 conditional knockout setting (Ross et al 2012). PCGF1 knockdown was shown to induce expression of HOXA cluster genes and led to a loss of H2AK119ub at the promoters of these genes.…”

Knockdown of Polycomb-Group RING Finger 6 Modulates Mouse Male Germ Cell Differentiation in Vitro

“…An increasing number of studies have demonstrated that the mammalian PCGFs play important roles in cell proliferation, differentiation, and tumorigenesis. For instance, PCGF1, also known as NSPc1, could promote tumor cell cycle progression and cell proliferation and also is necessary for the terminal differentiation of hematopoietic cells [7,8]. In contrast, PCGF2, also known as Mel-18, could inhibit the tumor cell proliferation and self-renewal activity of hematopoietic stem cells [9,10].…”