Department of Cell & Developmental Biology
Oregon Health & Science University
The transcriptional co-repressor, Rcor1, is a critical component of gene expression regulatory machinery. It interacts with two important histone modification enzymes and couples their activities during gene expression regulation. Although many transcription factors have been shown to use Rcor1 as a cofactor to regulate gene expression, it was not clear what biological functions were dependent upon Rcor1. To study Rcor1 function in vivo, I characterized three Rcor1 knockout mouse models that lacked Rcor1 globally, in the nervous system, or in the hematopoietic system respectively.
Nervous system conditional Rcor1 knockout did not show an obvious phenotype during development, likely due to compensation from Rcor2, another Rcor family member. Therefore, the function of Rcor1 in adult brain remains to be tested using different genetic models that disallow compensation. In contrast, I observed profoundly anemic and late gestation lethality in mice deleted globally for Rcor1, indicating that Rcor1 plays an important role in hematopoiesis. Specifically, definitive erythroid cells from mutant mice arrest at the transition from proerythroblast to basophilic erythroblast. Remarkably, Rcor1 null erythroid progenitors cultured in vitro form myeloid colonies instead of erythroid colonies. The mutant proerythroblasts also aberrantly express genes of the myeloid lineage as well as genes typical of hematopoietic stem cell (HSC) / progenitor cells. I show that the Colony Stimulating Factor 2 Receptor Beta subunit (Csf2rb), which codes for a receptor implicated in myeloid cytokine signaling, is a direct target for both Rcor1 and the transcription repressor Gfi1b in erythroid cells. In the absence of Rcor1, the Csf2rb gene is highly induced, and Rcor1-/- progenitors exhibit CSF2-dependent phospho-Stat5 hypersensitivity. Blocking this pathway can partially reduce myeloid colony formation by Rcor1 deficient erythroid progenitors. Thus, Rcor1 promotes erythropoiesis by repressing HSC/progenitor genes, as well as the genes and signaling pathways that lead to myeloid cell fate.
While the study with global Rcor1 knockout model demonstrates that the co-repressor Rcor1 is essential for maturation of definitive erythroid cells in the fetal liver, the embryonic lethality prevented me from studying other hematopoietic lineages. Because Rcor1 interacts with several transcription factors that are critically important for regulating multiple hematopoietic lineage differentiation, I also investigated Rcor1 function in adult hematopoiesis following its conditional deletion in vivo. Loss of Rcor1 expression in hematopoietic cells led to the rapid development of severe anemia due to a complete block of erythropoiesis downstream of committed erythroid progenitors. By contrast, production of megakaryocyte progenitors, megakaryocyte maturation and thrombopoiesis were maintained. In the myeloid lineage, neutrophil differentiation was completely abrogated in the absence of Rcor1 expression and monocytic cells were significantly expanded, resulting in a peripheral blood leukocytosis and a monocytic infiltration in the liver. Rcor1-deficient monocytic cells were less apoptotic and had cytokine-dependent progenitor activity. Together, these data demonstrate that Rcor1 is essential for both erythroid and myelomonocytic differentiation and that its loss of function gives rise to significant myelodysplasia. As indicated in the chapters, some of these studies were done in collaboration with Devorah Goldman and Harv Fleming at OHSU, experts in hematopoiesis.
School of Medicine
Yao, Huilan, "Critical roles for the co-repressor, Rcor1, in lineage determination" (2014). Scholar Archive. 3554.
Available for download on Sunday, July 30, 2017