The Corepressor Rcor1 Is Essential for Normal Myeloerythroid Lineage Differentiation

Abstract

Based on its physical interactions with histone-modifying enzymes, the transcriptional corepressor Rcor1 has been implicated in the epigenetic regulation blood cell development. Previously, we have demonstrated that Rcor1 is essential for the maturation of definitive erythroid cells and fetal survival. To determine the functional role of Rcor1 in steady-state hematopoiesis in the adult, we used a conditional knockout approach. Here, we show that the loss of Rcor1 expression results in the rapid onset of severe anemia due to a complete, cell autonomous block in the maturation of committed erythroid progenitors. By contrast, both the frequency of megakaryocyte progenitors and their capacity to produce platelets were normal. Although the frequency of common lymphoid progenitors and T cells was not altered, B cells were significantly reduced and showed increased apoptosis. However, Rcor1-deficient bone marrow sustained normal levels of B-cells following transplantation, indicating a non-cell autonomous requirement for Rcor1 in B-cell survival. Evaluation of the myelomonocytic lineage revealed an absence of mature neutrophils and a significant increase in the absolute number of monocytic cells. Rcor1-deficient monocytes were less apoptotic and showed~100-fold more colonyforming activity than their normal counterparts, but did not give rise to leukemia. Moreover, Rcor1 2/2 monocytes exhibited extensive, cytokine-dependent self-renewal and overexpressed genes associated with hematopoietic stem/progenitor cell expansion including Gata2, Meis1, and Hoxa9. Taken together, these data demonstrate that Rcor1 is essential for the normal differentiation of myeloerythroid progenitors and for appropriately regulating self-renewal activity in the monocyte lineage. STEM CELLS 2015;33:3304-3314 SIGNIFICANCE STATEMENTIn vitro interactions between histone modifying enzymes and the transcriptional co-repressor Rcor1 suggest it has an important role in the epigenetic regulation blood cell development. This study provides the first in vivo evidence that Rcor1 is essential for the normal production of mature red blood cells and neutrophils but not platelets. Rcor1-deficient monocytes are increased in number, have an enhanced capacity to self-renew, but remain cytokine dependent and do not give rise to leukemia. Rcor1 loss also leads to the aberrant expression of transcription factors that normally promote the replication of hematopoietic stem/progenitor cells. These findings demonstrate that Rcor1 is essential for red cell and neutrophil maturation while restricting the self-renewal potential of monocytes.

RCOR1 directly binds to MED28 and weakens its inducing effect on cancer stem cell‐like activity of oral cavity squamous cell carcinoma cells

“…To explore other potential functional partners of MED28, we predicted its potential partners with direct bindings (Figure 3A). Among the candidates, we noticed that RCOR1 is a stem cell differentiation‐related protein 11,12 . Interestingly, RCOR1 expression was significantly higher in SCC9/CD44 low cells than in SCC9/CD44 high cells (Figure 3B).…”

“…Thus, we further explored the functional partner of MED28 in OCSCC. Among the predicted partners, RCOR1 is a modulator of stem cell differentiation, which induces mouse embryonic stem cell differentiation 11 and normal myeloerythroid lineage differentiation 12 . We demonstrated that RCOR1 could suppress the CSC‐like properties of SCC9 cells and had direct interaction with MED28.…”

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity

“…Rcor1 also recruits the INSM1/Rcor1/2 complex, controlling the balance of proliferation and differentiation during brain development (20). In hematopoietic stem cells, loss of Rcor1 in adults leads to a complete block in erythroid and neutrophil differentiation (21). Although Rcor1 functions as an epigenetic and repressive factor in immune cells, its role in the regulation of Foxp3 + Tregs has not been studied.…”

The impact of Mir-9 regulation in normal and malignant hematopoiesis

“…It has been reported as an essential factor in normal differentiation of myeloerythroid progenitors, which regulates self-renewal activity in monocytes. 85 , 86 More studies should be done on RCOR1 expression in leukemia patients in order to determine its role in malignant hematopoiesis.…”